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a(CHEBI:nicotine)

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Entity

Name
nicotine
Namespace
chebi
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/chebi-names.belns

Appears in Networks 17

albuquerque2009 v1.0.0

This file encodes the article Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function by Albuquerque et al, 2009

Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. v1.0.0

Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System v1.0.0

Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine v1.0.1

Alzheimer's Disease: Targeting the Cholinergic System v1.0.0

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment v1.0.1

NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain v1.0.0

Neural Systems Governed by Nicotinic Acetylcholine Receptors: Emerging Hypotheses v1.0.0

Nicotinic Receptor Abnormalities of Alzheimer’s Disease: Therapeutic Implications v1.0.0

Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system v1.0.0

This document contains the curation of the review article Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system by Taly et al. 2009

Chaperoning α7 neuronal nicotinic acetylcholine receptors v1.0.0

Up-regulation of Nicotinic Receptors by Nicotine Varies with Receptor Subtype v1.0.0

Naturally-expressed nicotinic acetylcholine receptor subtypes v1.0.0

Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation v1.0.0

Anatabine lowers Alzheimer's Aβ production in vitro and in vivo v1.0.0

Discriminative Stimulus Properties of S(−)-Nicotine: “A Drug for All Seasons v1.0.0

Silencing of PMT expression caused a surge of anatabine accumulation in tobacco v1.0.0

In-Edges 70

composite(a(CHEBI:"amyloid-beta"), a(CHEBI:nicotine)) hasComponent a(CHEBI:nicotine) View Subject | View Object

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complex(a(CHEBI:nicotine), a(HBP:"alpha-4 beta-4 nAChR")) hasComponent a(CHEBI:nicotine) View Subject | View Object

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complex(a(CHEBI:nicotine), a(HBP:"alpha-4-containing nAChR")) hasComponent a(CHEBI:nicotine) View Subject | View Object

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a(HBP:"beta-2-containing nAChR") association a(CHEBI:nicotine) View Subject | View Object

The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57). PubMed:19126755

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a(HBP:"beta-2-containing nAChR") causesNoChange act(a(CHEBI:nicotine)) View Subject | View Object

The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57). PubMed:19126755

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a(MESH:Neurons) increases deg(a(CHEBI:nicotine)) View Subject | View Object

Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503). PubMed:19126755

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a(MESH:Skin) association act(a(CHEBI:nicotine)) View Subject | View Object

Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below. PubMed:19126755

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MeSH
Skin
Text Location
Review

bp(GO:"ERK1 and ERK2 cascade") increases act(a(CHEBI:nicotine)) View Subject | View Object

Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below. PubMed:19126755

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MeSH
Skin
Text Location
Review

bp(GO:"receptor signaling pathway via JAK-STAT") increases act(a(CHEBI:nicotine)) View Subject | View Object

Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below. PubMed:19126755

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MeSH
Skin
Text Location
Review

act(p(HGNC:CHRNA7)) association a(CHEBI:nicotine) View Subject | View Object

A principle component of genetic analysis of the contribution of alpha7 and alpha4beta2 nAChRs to the effects of nicotine was reported 15 years ago. The number of alpha-BGT binding sites (presumably alpha7 nAChRs) was shown to be highly correlated with sensitivity to nicotinic-induced seizures (105, 301, 303). PubMed:19126755

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MeSH
Seizures
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Review

p(HGNC:CHRNA7) regulates a(CHEBI:nicotine) View Subject | View Object

Several possibilities exist for the identity of the nAChR important to tolerance development. The strong positive correlation between alpha-BGT site number and sensitivity to nicotine-induced seizures among multiple mouse strains led to the suggestion that alpha7 nAChRs are critical to limit oral nicotine self-administration in mice (105, 301). PubMed:19126755

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complex(a(CHEBI:nicotine), p(HBP:"alpha-4 beta-2 nAChR")) hasComponent a(CHEBI:nicotine) View Subject | View Object

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composite(a(CHEBI:nicotine), g(HGNC:CHRNA4), g(HGNC:CHRNA6), g(HGNC:CHRNB2), g(HGNC:CHRNB3)) hasComponent a(CHEBI:nicotine) View Subject | View Object

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p(HGNC:ACHE) decreases act(a(CHEBI:nicotine)) View Subject | View Object

At the neuromuscular junction, nicotinic function is enhanced by inhibition of acetylcholinesterase (AChE), the enzyme that metabolizes the endogenous neurotransmitter ACh. PubMed:19126755

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MeSH
Neuromuscular Junction
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Review

path(HBP:neurotoxicity) association a(CHEBI:nicotine) View Subject | View Object

Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503). PubMed:19126755

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path(MESH:"Genetic Variation") association act(a(CHEBI:nicotine)) View Subject | View Object

Mice are particularly well-defined for their strain-specific complex genetic traits related to the effects of nicotine (105, 302) and morphological variations in the brain (e.g., Refs. 166, 167, 169). PubMed:19126755

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a(CHEBI:"amyloid-beta") decreases act(a(CHEBI:nicotine)) View Subject | View Object

The most comprehensive study of the effects of Abeta at different concentrations showed that at 10 pM, Abeta evoked an inward current mediated by rat alpha7 nAChRs expressed in X. laevis oocytes, whereas at 100 nM, Abeta blocked nicotine responses through desensitization (Dineley et al., 2002). PubMed:19293145

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a(CHEBI:"dihydro-beta-erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145

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a(CHEBI:"dihydro-beta-erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Nicotine protection of cultured rat cortical neu- rons against Abeta toxicity is blocked by the alpha4beta2 antagonist, dihydro-beta-erythroidine (Kihara et al., 1998). PubMed:19293145

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a(CHEBI:Mecamylamine) decreases act(a(CHEBI:nicotine)) View Subject | View Object

The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145

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a(MESH:Calcineurin) association act(a(CHEBI:nicotine)) View Subject | View Object

Stevens et al. (2003) showed that calcineurin is involved in nicotine neuroprotection. Abeta, through alpha7 nAChRs, increases Ca2+, which phosphorylates NMDARs via calcineurin and protein tyrosine phosphatase, nonreceptor type 5 (striatum-enriched) (Snyder et al., 2005). PubMed:19293145

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bp(GO:"calcium-mediated signaling") association a(CHEBI:nicotine) View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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Experimental Factor Ontology (EFO)
PC12

bp(GO:"negative regulation of apoptotic process") association a(CHEBI:nicotine) View Subject | View Object

Hepatic vagus nerve activity has recently been shown to protect hepatocytes from Fas-induced apoptosis via activation of alpha7 nAChRs (Hiramoto et al., 2008). Thus, nicotine seems to exert a general pro-survival action not only on neurons but also on non-neuronal cells, suggesting that the protection offered by nicotine against Abeta toxicity may therefore simply be the result of a general pro-survival response. PubMed:19293145

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MeSH
Liver

p(HGNC:CHRNA7) regulates act(a(CHEBI:nicotine)) View Subject | View Object

In SHSY5Y cells, RNA interference (RNAi) knockdown of alpha7 enhanced Abeta toxicity (Qi et al., 2007), and alpha7 antagonists, but not alpha4beta2 antagonists, block galantamine protection of cultured rat neurons (Kihara et al., 2004). Donepezil protects cultured rat cortical neurons against Abeta toxicity through both alpha7 and non-alpha7 nAChRs (Takada et al., 2003). It is therefore likely that alpha7 nAChRs are the primary mediators of nicotine neuroprotection, but in some cells, non-alpha7 subtypes are also likely to contribute. PubMed:19293145

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p(HGNC:CHRNA7) increases a(CHEBI:nicotine) View Subject | View Object

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145

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Experimental Factor Ontology (EFO)
PC12

composite(a(CHEBI:nicotine), complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) hasComponent a(CHEBI:nicotine) View Subject | View Object

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complex(a(CHEBI:nicotine), p(HGNC:CHRNA7)) hasComponent a(CHEBI:nicotine) View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(CHEBI:nicotine) View Subject | View Object

The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145

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act(p(HGNC:CHRNA4)) increases act(a(CHEBI:nicotine)) View Subject | View Object

For example, nicotine effectively protects wild-type mice, but not alpha4-knockout mice, against methamphetamine-evoked neurodegeneration (Ryan et al., 2001). PubMed:19293145

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composite(a(CHEBI:"3',5'-cyclic AMP"), p(FPLX:PKC)) regulates act(a(CHEBI:nicotine)) View Subject | View Object

The nicotine-induced nAChR up-regulation in human SH-EP1 cells heterologously expressing alpha7 nAChRs is mediated by cAMP and protein kinase C (PKC) (Nuutinen et al., 2006). The effects of long-term nicotine treatment on nAChR expression in rat brain differs for receptors of different subtype composition (most pronounced up-regulation being observed for alpha4beta2 receptors) and for different brain regions (Nguyen et al., 2003). PubMed:19293145

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composite(p(FPLX:ERK), p(FPLX:RAF), p(FPLX:RAS), p(HGNC:MAP2K1)) increases act(a(CHEBI:nicotine)) View Subject | View Object

Paradoxically, Abeta also activates the MAPK pathway through an alpha7-dependent pathway (Dineley et al., 2001; Bell et al., 2004). In human oral keratinocytes, the Ras/Raf/mitogen-activated protein kinase kinase 1/ERK pathway cooperates with the nicotine activation of the JAK/STAT-3 pathway (Arredondo et al., 2006); the Ras pathway induces STAT-3 upregulation whereas the JAK/STAT-3 pathway phosphorylates STAT-3. PubMed:19293145

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p(FPLX:ERK) association a(CHEBI:nicotine) View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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Experimental Factor Ontology (EFO)
PC12

act(p(HGNC:STAT3)) association act(a(CHEBI:nicotine)) View Subject | View Object

JAK-2, another early target in the nicotine neuroprotection pathway that may mediate signaling between the nAChR and the PI3K pathway (Shaw et al., 2002), may link nAChR activation with the JAK/signal transducer and activator of transcription 3 (STAT-3) protective pathway. JAK-2 is also activated by nicotine in non-neuronal cells such as nAChR-bearing keratinocytes (Arredondo et al., 2006). In a microarray study, expression of 8 of 33 JAK/STAT pathway genes was altered when human bronchial epithelial cells were exposed to 5 microM nicotine for 4 to 10 h (Tsai et al., 2006). Thus, the JAK-2/STAT-3 pathway is activated by exposure to nicotine. PubMed:19293145

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p(HGNC:JAK2) increases act(a(CHEBI:nicotine)) View Subject | View Object

JAK-2, another early target in the nicotine neuroprotection pathway that may mediate signaling between the nAChR and the PI3K pathway (Shaw et al., 2002), may link nAChR activation with the JAK/signal transducer and activator of transcription 3 (STAT-3) protective pathway. JAK-2 is also activated by nicotine in non-neuronal cells such as nAChR-bearing keratinocytes (Arredondo et al., 2006). In a microarray study, expression of 8 of 33 JAK/STAT pathway genes was altered when human bronchial epithelial cells were exposed to 5 microM nicotine for 4 to 10 h (Tsai et al., 2006). Thus, the JAK-2/STAT-3 pathway is activated by exposure to nicotine. PubMed:19293145

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act(p(HGNC:JAK2)) regulates act(a(CHEBI:nicotine)) View Subject | View Object

Nicotine induced phosphorylation of STAT-3 (signal transducer and activator of transcription 3) in peritoneal macrophages is mediated by an alpha7-dependent activation of JAK-2, as part of the anti-inflammatory action of vagal nerve stimulation (de Jonge et al., 2005). PubMed:19293145

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Cell Ontology (CL)
peritoneal macrophage

p(FPLX:PI3K) increases act(a(CHEBI:nicotine)) View Subject | View Object

The neuroprotective effects of nicotine are blocked by inhibitors of either PI3K or SRC family kinases, and nicotine evokes an increase in levels of phosphorylated AKT, B-cell chronic lymphocytic leukemia/lymphoma (BCL2), and BCL-2-like protein (Shimohama and Kihara, 2001), which are further downstream in the PI3K/AKT pathway (Fig. 3). PubMed:19293145

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p(FPLX:SRC) increases act(a(CHEBI:nicotine)) View Subject | View Object

The neuroprotective effects of nicotine are blocked by inhibitors of either PI3K or SRC family kinases, and nicotine evokes an increase in levels of phosphorylated AKT, B-cell chronic lymphocytic leukemia/lymphoma (BCL2), and BCL-2-like protein (Shimohama and Kihara, 2001), which are further downstream in the PI3K/AKT pathway (Fig. 3). PubMed:19293145

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p(HGNC:TNF) increases act(a(CHEBI:nicotine)) View Subject | View Object

There is evidence that nicotine’s neuroprotective effects can be mediated through tumor necrosis factor-alpha (TNF-alpha). Application of either nicotine or TNF-alpha protects cultured mouse embryonic cortical neurons from N-methyl-D-aspartate (NMDA) toxicity, but coapplication of both does not. PubMed:19293145

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p(HGNCGENEFAMILY:"Inositol 1,4,5-triphosphate receptors") association a(CHEBI:nicotine) View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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Experimental Factor Ontology (EFO)
PC12

p(HGNCGENEFAMILY:"Ryanodine receptors") association a(CHEBI:nicotine) View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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Experimental Factor Ontology (EFO)
PC12

act(p(RGD:Chrna7)) regulates act(a(CHEBI:nicotine)) View Subject | View Object

Shortterm nicotine application also induces phosphorylation of p44/42MAPK, p38MAPK, and STAT-3 and was mediated mostly by alpha7 nAChRs in rat vascular smooth muscle cells (Wada et al., 2007). It is noteworthy that the JAK-2/STAT-3 pathway also mediates the mitogenic effects of insulin, a process recently implicated in AD (Li and Ho¨lscher, 2007). PubMed:19293145

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Cell Ontology (CL)
vascular associated smooth muscle cell

complex(a(CHEBI:nicotine), p(FPLX:CHRN)) hasComponent a(CHEBI:nicotine) View Subject | View Object

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complex(a(CHEBI:nicotine), p(FPLX:CHRM)) hasComponent a(CHEBI:nicotine) View Subject | View Object

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complex(a(CHEBI:nicotine), p(HGNC:CHRNA4)) hasComponent a(CHEBI:nicotine) View Subject | View Object

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a(CHEBI:"amyloid-beta polypeptide 42") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Regardless of the exact effect of Abeta1–42 on receptor activity, it does seem to block the activation by nicotine and, consistent with the cytoprotective nature of this interaction, amyloid deposition limits neuroprotection151. This phenomenon may explain at least part of the neurotoxicity that is associated with Abeta1–42 (ReF. 156). PubMed:19721446

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Review

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Nicotine self administration is also reduced in rats by dihydro-beta erythroidine (DHbetae), a selective alpha4beta2 antagonist199. in this context, partial agonists may substitute for the desired effects of nicotine and antagonize its reinforcing properties163,200. PubMed:19721446

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p(HGNC:CHRNB4) association act(a(CHEBI:nicotine)) View Subject | View Object

Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107 PubMed:19721446

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MeSH
Corpus Striatum
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Review

bp(MESH:Neuroprotection) association a(CHEBI:nicotine) View Subject | View Object

The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151. PubMed:19721446

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Experimental Factor Ontology (EFO)
PC12
Text Location
Review

p(HGNC:CHRNA4) increases act(a(CHEBI:nicotine)) View Subject | View Object

in α4- and β2-knockout mice, the responses of raphe neurons to nicotine is abolished, together with nicotine-elicited antinociception228, and α4-hypersensitive knock-in mice show nicotine hypersensitivity in the supraspinal control (hot-plate assay), but not in the spinal control (tail flick assay)229. PubMed:19721446

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p(HGNC:CHRNA5) association act(a(CHEBI:nicotine)) View Subject | View Object

Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107 PubMed:19721446

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MeSH
Corpus Striatum
Text Location
Review

p(HGNC:CHRNB2) increases act(a(CHEBI:nicotine)) View Subject | View Object

in α4- and β2-knockout mice, the responses of raphe neurons to nicotine is abolished, together with nicotine-elicited antinociception228, and α4-hypersensitive knock-in mice show nicotine hypersensitivity in the supraspinal control (hot-plate assay), but not in the spinal control (tail flick assay)229. PubMed:19721446

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act(p(FPLX:"CAMK2_complex")) increases act(a(CHEBI:nicotine)) View Subject | View Object

Also, α7- and non-α7-containing nicotinic receptors directly or indirectly (through GABAergic interneurons) modulate serotonin release in spinal cord slices230. However, the identity of the receptors that are responsible for the spinal control of nociception is currently unknown. in this process, the nicotine-induced antinociception seems to be mediated primarily by activation of calcium– calmodulin-dependent protein kinase 2, but this is not the case for supraspinal nociception control229. PubMed:19721446

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p(HGNC:CHRNA2) association act(a(CHEBI:nicotine)) View Subject | View Object

Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107 PubMed:19721446

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MeSH
Corpus Striatum
Text Location
Review

p(HGNC:STAT3, pmod(Ph)) association a(CHEBI:nicotine) View Subject | View Object

Nicotine has been shown to modulate inflammation by affecting STAT3 phosphorylation (Chatterjee et al., 2009; Hosur and Loring, 2011) and by opposing NFkB activation (Leite et al., 2010; Zhou et al., 2010) PubMed:23178521

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complex(a(CHEBI:nicotine), a(MESH:"Receptors, Nicotinic")) hasComponent a(CHEBI:nicotine) View Subject | View Object

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complex(a(CHEBI:nicotine), a(MESH:"nicotinic receptor alpha4beta2")) hasComponent a(CHEBI:nicotine) View Subject | View Object

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p(HGNC:QPRT) increases a(CHEBI:nicotine) View Subject | View Object

To shed further light on pathway regulation, the question was asked about whether alteration of nicotine and anatabine content would affect the expression of other key enzyme, namely QPRT, which is a key enzyme in the biosynthesis of another precursor of nicotine, and also the key enzyme of anatabine (Fig. 1). PubMed:19165623

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a(CHEBI:"(-)-lobeline") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Lobeline has, however, been shown to antagonize partially the stimulus effects of (-)-nicotine and S(+)-methamphetamine ([64, 160]; but see [66]). PubMed:28391535

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a(CHEBI:bupropion) decreases act(a(CHEBI:nicotine)) View Subject | View Object

Other studies have reported that bupropion blocked the acute effects of (-)-nicotine in a number of behavioral assays in mice (e.g., [171, 172]) PubMed:28391535

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a(CHEBI:Hexamethonium) negativeCorrelation act(a(CHEBI:nicotine)) View Subject | View Object

. It should be noted that hexamethonium, at relatively low doses, does not block the stimulus effects of (-)-nicotine but when administered at high doses has occasionally been reported to attenuate nicotine-like responding; probably the result of penetration into the CNS of a small proportion of the administered dose of drug (e.g., [35, 38, 64, 106, 146]) PubMed:28391535

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a(CHEBI:Mecamylamine) decreases act(a(CHEBI:nicotine)) View Subject | View Object

This conclusion is based on the fact that the stimulus effects of nicotine are convincingly blocked by (a) mecamylamine, a voltage dependent noncompetitive channel blocker at nicotinic receptors (Fig. 3; Table 4) and (b) dihydro-β-erythrodine (DHβE), a nicotinic receptor antagonist that shows high affinity for the nAChR α4β2 subunit (Fig. 3; Table 5) but not by methyllycaconitine (MLA), a α7 nicotinic receptor antagonist (Table 5). PubMed:28391535

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a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

This conclusion is based on the fact that the stimulus effects of nicotine are convincingly blocked by (a) mecamylamine, a voltage dependent noncompetitive channel blocker at nicotinic receptors (Fig. 3; Table 4) and (b) dihydro-β-erythrodine (DHβE), a nicotinic receptor antagonist that shows high affinity for the nAChR α4β2 subunit (Fig. 3; Table 5) but not by methyllycaconitine (MLA), a α7 nicotinic receptor antagonist (Table 5). PubMed:28391535

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a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Research results summarized in Table 5 indicate that DHβE effectively blocked the stimulus effects of (-)-nicotine in rats or mice (but see exceptions reported by [120, 121]). PubMed:28391535

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a(MESH:Tobacco) hasComponent a(CHEBI:nicotine) View Subject | View Object

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a(PUBCHEM:5288811) causesNoChange act(a(CHEBI:nicotine)) View Subject | View Object

This conclusion is based on the fact that the stimulus effects of nicotine are convincingly blocked by (a) mecamylamine, a voltage dependent noncompetitive channel blocker at nicotinic receptors (Fig. 3; Table 4) and (b) dihydro-β-erythrodine (DHβE), a nicotinic receptor antagonist that shows high affinity for the nAChR α4β2 subunit (Fig. 3; Table 5) but not by methyllycaconitine (MLA), a α7 nicotinic receptor antagonist (Table 5). PubMed:28391535

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a(PUBCHEM:5288811) causesNoChange act(a(CHEBI:nicotine)) View Subject | View Object

Table 5 presents results of MLA/(-)-nicotine combination studies and shows that MLA failed to alter the stimulus effects of (-)-nicotine in rats or mice (but see partial antagonism reported by Quarta et al. [126]) PubMed:28391535

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path(MESH:"Motor Activity") negativeCorrelation a(CHEBI:nicotine) View Subject | View Object

For example, in rodents, administration of low doses of nicotine produced increased motor activity whereas high doses produced decreased motor activity (e.g.,[17, 18]) PubMed:28391535

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a(UNIPROT:Q9SEH4) increases a(CHEBI:nicotine) View Subject | View Object

N-methyl-Δ1-pyrrolinium is synthesized from arginine and/ or ornithine, and is controlled by putrescine N-methyl transferase (PMT), which is the key enzyme in diverting metabolism towards the biosynthesis of nicotine and others alkaloids [12, 13]. PubMed:19165623

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a(UNIPROT:Q9SEH4) increases a(CHEBI:nicotine) View Subject | View Object

Experiments involving RNA-mediated gene silencing with transgenic Nicotiana plants have shown that a decrease in PMT expression levels can lead to low nicotine content PubMed:19165623

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complex(a(CHEBI:"1-methylpyrrolinium"), a(CHEBI:"nicotinic acid")) increases a(CHEBI:nicotine) View Subject | View Object

Nicotine is synthesized through condensation of two transitory compounds, N-methyl-Δ1-pyrrolinium and nicotinic acid [5, 12]. PubMed:19165623

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a(CHEBI:nicotine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

The other subtype of AChR is the fast ionotropic cationic nicotinic receptor channel (nAChR). These receptors are sensitive to activation by nicotine and have ion channels whose activity is induced in the micro- to submicrosecond range. PubMed:19126755

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a(CHEBI:nicotine) decreases deg(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits", loc(GO:"endoplasmic reticulum"))) View Subject | View Object

Also, the continuous exposure of cells to nicotine increases nAChR surface expression by reducing degradation of the intracellular pool of receptors (367, 394). PubMed:19126755

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a(CHEBI:nicotine) increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

In the smoker’s brain, upregulation can increase high-affinity nicotine binding by nearly fourfold relative to age- and gender-matched controls that have not been exposed to nicotine (373, 421). The mechanism by which nicotine increases the total number of high-affinity nAChRs, though poorly defined, is highly conserved among species. PubMed:19126755

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a(CHEBI:nicotine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways. PubMed:19126755

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Keratinocytes
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a(CHEBI:nicotine) causesNoChange p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396) PubMed:19126755

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a(CHEBI:nicotine) regulates p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression PubMed:19126755

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a(CHEBI:nicotine) regulates act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression PubMed:19126755

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a(CHEBI:nicotine) causesNoChange a(MESH:Manduca) View Subject | View Object

One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier. PubMed:19126755

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a(CHEBI:nicotine) association path(HBP:neurotoxicity) View Subject | View Object

Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503). PubMed:19126755

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a(CHEBI:nicotine) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

The receptor that exhibits the greatest upregulation when exposed to nicotine is the alpha4beta2 nAChR. Receptors assembled from this subunit combination form the highaffinity nicotine binding site (151, 215) and account for the vast majority of upregulated sites in the brain of smokers (55). PubMed:19126755

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a(CHEBI:nicotine) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

transfection of cells with the beta4 and alpha2 nAChR subunits or expression of these in Xenopus oocytes leads to high-affinity nicotine-binding receptors that upregulate in response to prolonged exposure to nicotine (113, 184, 215). PubMed:19126755

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a(CHEBI:nicotine) increases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped. PubMed:19126755

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a(CHEBI:nicotine) decreases act(p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped. PubMed:19126755

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a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), p(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

The receptor that exhibits the greatest upregulation when exposed to nicotine is the alpha4beta2 nAChR. Receptors assembled from this subunit combination form the highaffinity nicotine binding site (151, 215) and account for the vast majority of upregulated sites in the brain of smokers (55). PubMed:19126755

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a(CHEBI:nicotine) increases a(HBP:"alpha-3 beta-2 nAChR") View Subject | View Object

For instance, prolonged exposure of HEK293 cells to saturating nicotine concentrations increased by 6- and 1.5-fold, respectively, the expression of alpha3beta2 and alpha3beta4 nAChRs.Similarly, while alpha4beta2 nAChRs upregulate strongly, alpha4beta4 nAChRs upregulate poorly in response to continuous exposure to nicotine. PubMed:19126755

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HEK293
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a(CHEBI:nicotine) increases a(HBP:"alpha-3 beta-4 nAChR") View Subject | View Object

For instance, prolonged exposure of HEK293 cells to saturating nicotine concentrations increased by 6- and 1.5-fold, respectively, the expression of alpha3beta2 and alpha3beta4 nAChRs.Similarly, while alpha4beta2 nAChRs upregulate strongly, alpha4beta4 nAChRs upregulate poorly in response to continuous exposure to nicotine. PubMed:19126755

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HEK293
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a(CHEBI:nicotine) decreases complex(p(HGNC:CHRNA6), p(HGNC:CHRNB3)) View Subject | View Object

Prolonged treatment of rodents and monkeys with nicotine downregulates the expression of alpha6beta3-containing nAChRs in the brain (257, 311, 332). However, in heterologous culture systems, nicotine appears to upregulate the expression of receptors assembled from alpha4/alpha6/beta2/beta3 input cDNA (363), and this may depend on numerous factors including ligand concentrations (483). PubMed:19126755

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Brain
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a(CHEBI:nicotine) increases act(p(FPLX:PI3K)) View Subject | View Object

An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469). PubMed:19126755

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Central Nervous System
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Parasympathetic Nervous System
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a(CHEBI:nicotine) increases act(p(FPLX:PKA)) View Subject | View Object

An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469). PubMed:19126755

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Central Nervous System
MeSH
Parasympathetic Nervous System
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a(CHEBI:nicotine) increases act(p(FPLX:PKC)) View Subject | View Object

An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469). PubMed:19126755

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Central Nervous System
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Parasympathetic Nervous System
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a(CHEBI:nicotine) increases act(p(FPLX:"CAMK2_complex")) View Subject | View Object

An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469). PubMed:19126755

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Central Nervous System
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Parasympathetic Nervous System
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act(a(CHEBI:nicotine)) increases act(p(FPLX:CREB)) View Subject | View Object

Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354). PubMed:19126755

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PC12 Cells
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act(a(CHEBI:nicotine)) increases act(p(HGNC:ATF2)) View Subject | View Object

Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354). PubMed:19126755

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PC12 Cells
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act(a(CHEBI:nicotine)) increases act(p(RGD:Elk1)) View Subject | View Object

Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354). PubMed:19126755

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Hippocampus
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act(a(CHEBI:nicotine)) increases act(p(HGNC:STAT3)) View Subject | View Object

Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354). PubMed:19126755

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Macrophages
MeSH
Skin
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Review

act(a(CHEBI:nicotine)) association a(MESH:Skin) View Subject | View Object

Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below. PubMed:19126755

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Skin
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act(a(CHEBI:nicotine)) regulates bp(GO:"inflammatory response") View Subject | View Object

Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401). PubMed:19126755

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Intestines
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a(CHEBI:nicotine) decreases path(MESH:"Colitis, Ulcerative") View Subject | View Object

Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401). PubMed:19126755

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Intestines
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a(CHEBI:nicotine) decreases path(MESH:"Inflammatory Bowel Diseases") View Subject | View Object

Notably, mice with a null mutation in the gene that encodes the alpha5 nAChR subunit exhibit enhanced sensitivity to induction of inflammatory bowel disease relative to controls (353). Despite increased sensitivity to disease initiation, administration of transdermal nicotine remains effective in attenuating the disease process. Therefore, again nicotine appears to impact on inflammatory processes with considerable specificity and tissue dependency. PubMed:19126755

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a(CHEBI:nicotine) decreases sec(p(HGNC:TNF)) View Subject | View Object

Notably, nicotine pretreatment of rat adipocytes (279) reduces the release of TNF-alpha as well as free fatty acids and the adipokine adiponectin (whose function is not known, although its levels change in metabolic syndrome). PubMed:19126755

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Adipocytes
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act(a(CHEBI:nicotine)) association path(MESH:"Genetic Variation") View Subject | View Object

Mice are particularly well-defined for their strain-specific complex genetic traits related to the effects of nicotine (105, 302) and morphological variations in the brain (e.g., Refs. 166, 167, 169). PubMed:19126755

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a(CHEBI:nicotine) causesNoChange path(MESH:"Alzheimer Disease") View Subject | View Object

In human trials, nicotine showed little efficacy in ameliorating AD symptoms (437). However, treatment was initiated after diagnosis of symptoms, and there is both epidemiological data and direct evidence from animal models that this is too late (106, 346, 396). PubMed:19126755

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a(CHEBI:nicotine) causesNoChange p(MGI:Chrna4) View Subject | View Object

First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396) PubMed:19126755

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a(CHEBI:nicotine) decreases act(a(CHEBI:"NS-398")) View Subject | View Object

A link between alpha4 nAChRs and Cox2 was suggested by the observation that interneurons in the hippocampus coexpress both proteins (165). A mechanistic connection was inferred when long-term treatment of aged animals with NS398 promoted retention of alpha4 nAChR expression in the brain, an effect that was antagonized by the coadministration of nicotine. PubMed:19126755

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a(CHEBI:nicotine) decreases bp(GO:"neuron death") View Subject | View Object

More direct evidence of the protective effects of nicotine in this disease process comes from studies in primates, where oral nicotine reduces the nigrostriatal neuronal loss observed in chemically induced PD (384, 385). PubMed:19126755

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Parkinson Disease
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a(CHEBI:nicotine) decreases bp(GO:"neuron death") View Subject | View Object

However, in rodent and nonprimate animal models, nicotine has been shown to enhance striatal dopamine release and to prevent toxin-induced degeneration of dopaminergic neurons (384, 385). PubMed:19126755

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Corpus Striatum
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a(CHEBI:nicotine) increases sec(a(CHEBI:dopamine)) View Subject | View Object

However, in rodent and nonprimate animal models, nicotine has been shown to enhance striatal dopamine release and to prevent toxin-induced degeneration of dopaminergic neurons (384, 385). PubMed:19126755

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Corpus Striatum
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a(CHEBI:nicotine) increases path(MESH:"Behavior, Addictive") View Subject | View Object

Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression PubMed:19126755

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a(CHEBI:nicotine) increases path(MESH:Craving) View Subject | View Object

In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped. PubMed:19126755

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a(CHEBI:nicotine) increases path(MESH:Anxiety) View Subject | View Object

In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped. PubMed:19126755

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a(CHEBI:nicotine) association act(p(HGNC:CHRNA7)) View Subject | View Object

A principle component of genetic analysis of the contribution of alpha7 and alpha4beta2 nAChRs to the effects of nicotine was reported 15 years ago. The number of alpha-BGT binding sites (presumably alpha7 nAChRs) was shown to be highly correlated with sensitivity to nicotinic-induced seizures (105, 301, 303). PubMed:19126755

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Seizures
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a(CHEBI:nicotine) association a(HBP:"beta-2-containing nAChR") View Subject | View Object

The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57). PubMed:19126755

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a(CHEBI:nicotine) increases act(p(FPLX:CHRN)) View Subject | View Object

Activation and desensitization of nAChRs by bath-applied nicotine also increases LTD induced by a stimulus train PubMed:17009926

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a(CHEBI:nicotine) increases p(FPLX:CHRN) View Subject | View Object

This puzzle does not yet have a complete answer, but it is clear that chronic nicotine increases the number of nAChRs themselves (Marks et al., 1983; Schwartz and Kellar, 1983) PubMed:21482353

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a(CHEBI:nicotine) association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145

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a(CHEBI:nicotine) increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

It is now well established that exposure to nicotine results in increased expression of nAChRs in brain and in cultured cells (for review, see Gentry and Lukas, 2002). Exposure of human neuroblastoma SH-SY5Y cells (which express ganglionic alpha7 and alpha3* nAChRs), human TE671/RD cells, or mouse BC3H-1 cells (which express muscle-type nAChRs) to nicotine for up to 120 h induces a dose- and time-dependent increase in surface ACh and alpha-bungarotoxin (alpha-BTX) binding not attributable to changes in mRNA levels (Ke et al., 1998). PubMed:19293145

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a(CHEBI:nicotine) increases bp(MESH:Neuroprotection) View Subject | View Object

The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145

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act(a(CHEBI:nicotine)) increases bp(MESH:Neuroprotection) View Subject | View Object

The neuroprotective effects of nicotine are blocked by inhibitors of either PI3K or SRC family kinases, and nicotine evokes an increase in levels of phosphorylated AKT, B-cell chronic lymphocytic leukemia/lymphoma (BCL2), and BCL-2-like protein (Shimohama and Kihara, 2001), which are further downstream in the PI3K/AKT pathway (Fig. 3). PubMed:19293145

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act(a(CHEBI:nicotine)) increases bp(MESH:Neuroprotection) View Subject | View Object

JAK-2, another early target in the nicotine neuroprotection pathway that may mediate signaling between the nAChR and the PI3K pathway (Shaw et al., 2002), may link nAChR activation with the JAK/signal transducer and activator of transcription 3 (STAT-3) protective pathway. JAK-2 is also activated by nicotine in non-neuronal cells such as nAChR-bearing keratinocytes (Arredondo et al., 2006). In a microarray study, expression of 8 of 33 JAK/STAT pathway genes was altered when human bronchial epithelial cells were exposed to 5 microM nicotine for 4 to 10 h (Tsai et al., 2006). Thus, the JAK-2/STAT-3 pathway is activated by exposure to nicotine. PubMed:19293145

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act(a(CHEBI:nicotine)) increases bp(MESH:Neuroprotection) View Subject | View Object

There is evidence that nicotine’s neuroprotective effects can be mediated through tumor necrosis factor-alpha (TNF-alpha). Application of either nicotine or TNF-alpha protects cultured mouse embryonic cortical neurons from N-methyl-D-aspartate (NMDA) toxicity, but coapplication of both does not. PubMed:19293145

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a(CHEBI:nicotine) increases bp(MESH:Neuroprotection) View Subject | View Object

It has been shown that the alpha7 receptors, but not the alpha3beta2 receptors, specifically trigger calcium release from intracellular stores by activating ryanodine receptors. Such a specific functional coupling of alpha7 receptors and ryanodine-sensitive stores may provide another site of therapeutic intervention. However, the sustained calcium rise seen in these cells upon prolonged nicotine administration, which is more likely to be of relevance to neuroprotection than short-term responses, is more dependent upon the activation of inositol 1,4,5-triphosphate receptors (Dajas-Bailador et al., 2002a), which are also a target for phosphorylation by FYN (Cui et al., 2004). PubMed:19293145

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a(CHEBI:nicotine) decreases path(HBP:neurotoxicity) View Subject | View Object

The discovery that nicotine, a ligand acting at nAChRs, and its mimetics can protect neurons against Abeta toxicity (Kihara et al., 1998) is of interest, especially in view of the observation that nicotine also enhances cognition (Rusted et al., 2000). Nicotinic receptors play a particularly prominent role in nicotine protection. The protective effect is blocked by the nicotinic antagonists dihydro-beta-erythroidine and mecamylamine (Kihara et al., 2001; Takada- Takatori et al., 2006). PubMed:19293145

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a(CHEBI:nicotine) increases a(CHEBI:acetylcholine) View Subject | View Object

It is now well established that exposure to nicotine results in increased expression of nAChRs in brain and in cultured cells (for review, see Gentry and Lukas, 2002). Exposure of human neuroblastoma SH-SY5Y cells (which express ganglionic alpha7 and alpha3* nAChRs), human TE671/RD cells, or mouse BC3H-1 cells (which express muscle-type nAChRs) to nicotine for up to 120 h induces a dose- and time-dependent increase in surface ACh and alpha-bungarotoxin (alpha-BTX) binding not attributable to changes in mRNA levels (Ke et al., 1998). PubMed:19293145

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SH-SY5Y

a(CHEBI:nicotine) increases complex(a(MESH:Bungarotoxins), p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

It is now well established that exposure to nicotine results in increased expression of nAChRs in brain and in cultured cells (for review, see Gentry and Lukas, 2002). Exposure of human neuroblastoma SH-SY5Y cells (which express ganglionic alpha7 and alpha3* nAChRs), human TE671/RD cells, or mouse BC3H-1 cells (which express muscle-type nAChRs) to nicotine for up to 120 h induces a dose- and time-dependent increase in surface ACh and alpha-bungarotoxin (alpha-BTX) binding not attributable to changes in mRNA levels (Ke et al., 1998). PubMed:19293145

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SH-SY5Y

act(a(CHEBI:nicotine)) increases p(HGNC:CHRNA7) View Subject | View Object

The nicotine-induced nAChR up-regulation in human SH-EP1 cells heterologously expressing alpha7 nAChRs is mediated by cAMP and protein kinase C (PKC) (Nuutinen et al., 2006). The effects of long-term nicotine treatment on nAChR expression in rat brain differs for receptors of different subtype composition (most pronounced up-regulation being observed for alpha4beta2 receptors) and for different brain regions (Nguyen et al., 2003). PubMed:19293145

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a(CHEBI:nicotine) decreases act(a(CHEBI:thapsigargin)) View Subject | View Object

Nicotine protects SH-SY5Y cells from cell death induced by thapsigargin, an inhibitor of the sarcoplasmic-reticulum calcium pump (Arias et al., 2004). PubMed:19293145

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SH-SY5Y

act(a(CHEBI:nicotine)) decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

For example, nicotine effectively protects wild-type mice, but not alpha4-knockout mice, against methamphetamine-evoked neurodegeneration (Ryan et al., 2001). PubMed:19293145

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a(CHEBI:nicotine) association bp(GO:"negative regulation of apoptotic process") View Subject | View Object

Hepatic vagus nerve activity has recently been shown to protect hepatocytes from Fas-induced apoptosis via activation of alpha7 nAChRs (Hiramoto et al., 2008). Thus, nicotine seems to exert a general pro-survival action not only on neurons but also on non-neuronal cells, suggesting that the protection offered by nicotine against Abeta toxicity may therefore simply be the result of a general pro-survival response. PubMed:19293145

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MeSH
Liver

act(a(CHEBI:nicotine)) increases p(FPLX:AKT, pmod(Ph)) View Subject | View Object

The neuroprotective effects of nicotine are blocked by inhibitors of either PI3K or SRC family kinases, and nicotine evokes an increase in levels of phosphorylated AKT, B-cell chronic lymphocytic leukemia/lymphoma (BCL2), and BCL-2-like protein (Shimohama and Kihara, 2001), which are further downstream in the PI3K/AKT pathway (Fig. 3). PubMed:19293145

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act(a(CHEBI:nicotine)) increases p(HGNC:BCL2) View Subject | View Object

The neuroprotective effects of nicotine are blocked by inhibitors of either PI3K or SRC family kinases, and nicotine evokes an increase in levels of phosphorylated AKT, B-cell chronic lymphocytic leukemia/lymphoma (BCL2), and BCL-2-like protein (Shimohama and Kihara, 2001), which are further downstream in the PI3K/AKT pathway (Fig. 3). PubMed:19293145

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act(a(CHEBI:nicotine)) increases p(HGNC:BCL2L1) View Subject | View Object

The neuroprotective effects of nicotine are blocked by inhibitors of either PI3K or SRC family kinases, and nicotine evokes an increase in levels of phosphorylated AKT, B-cell chronic lymphocytic leukemia/lymphoma (BCL2), and BCL-2-like protein (Shimohama and Kihara, 2001), which are further downstream in the PI3K/AKT pathway (Fig. 3). PubMed:19293145

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a(CHEBI:nicotine) increases p(HGNC:BAX, pmod(Ph)) View Subject | View Object

The AD therapeutic AChE inhibitors donepezil, galantamine, and tacrine increase BCL2 expression when applied to cultured neuronal cells (Arias et al., 2004; Takada-Takatori et al., 2006). In these cells, nicotine promotes cell survival and causes the phosphorylation of the proapoptotic protein Bcl2-associated X protein (BAX), through the PI3K/AKT pathway, reducing the movement of BAX from the cytosol to the mitochondria and inhibiting its apoptotic activity (Xin and Deng, 2005). PubMed:19293145

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MeSH
Neurons

a(CHEBI:nicotine) decreases bp(GO:"apoptotic process") View Subject | View Object

The AD therapeutic AChE inhibitors donepezil, galantamine, and tacrine increase BCL2 expression when applied to cultured neuronal cells (Arias et al., 2004; Takada-Takatori et al., 2006). In these cells, nicotine promotes cell survival and causes the phosphorylation of the proapoptotic protein Bcl2-associated X protein (BAX), through the PI3K/AKT pathway, reducing the movement of BAX from the cytosol to the mitochondria and inhibiting its apoptotic activity (Xin and Deng, 2005). PubMed:19293145

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Neurons

a(CHEBI:nicotine) decreases bp(GO:"apoptotic process") View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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PC12

a(CHEBI:nicotine) decreases tloc(p(HGNC:BAX), fromLoc(GO:cytosol), toLoc(GO:mitochondrion)) View Subject | View Object

The AD therapeutic AChE inhibitors donepezil, galantamine, and tacrine increase BCL2 expression when applied to cultured neuronal cells (Arias et al., 2004; Takada-Takatori et al., 2006). In these cells, nicotine promotes cell survival and causes the phosphorylation of the proapoptotic protein Bcl2-associated X protein (BAX), through the PI3K/AKT pathway, reducing the movement of BAX from the cytosol to the mitochondria and inhibiting its apoptotic activity (Xin and Deng, 2005). PubMed:19293145

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Neurons

a(CHEBI:nicotine) increases act(p(HGNC:BAD)) View Subject | View Object

In lung cancer cells, nicotine also exerts an antiapoptotic effect through activating BCL2-antagonist of cell death (BAD), a process that is inhibited by blockers of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway or the PI3K/AKT pathway (Jin et al., 2004). PubMed:19293145

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lung cancer cell line

a(CHEBI:nicotine) increases act(p(FPLX:PI3K)) View Subject | View Object

For instance, over-expressing PI3K in Drosophila melanogaster neurons in situ results in an increase in functional synapses as well as synaptic sprouting (Martín-Pen˜ a et al., 2006). Thus it is possible that nicotine’s activation of the PI3K pathway results in increased synaptic stability, and it would be of interest to explore this further in vertebrates. Thus, the evidence suggests that activation of nAChRs activates the PI3K/AKT pathway to favor antiapoptotic pathways and possibly induce synaptogenesis. PubMed:19293145

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a(CHEBI:nicotine) increases complex(p(FPLX:"PI3K_p85"), p(HGNC:CHRNA7), p(HGNC:FYN)) View Subject | View Object

The neuroprotective activation of the PI3K/AKT pathway by nicotine involves the tyrosine kinase FYN, which physically interacts with alpha7 nAChRs, and the p85 subunit of PI3K in rat fetal cortical neurons in culture (Kihara et al., 2001). PubMed:19293145

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act(a(CHEBI:nicotine)) association act(p(HGNC:STAT3)) View Subject | View Object

JAK-2, another early target in the nicotine neuroprotection pathway that may mediate signaling between the nAChR and the PI3K pathway (Shaw et al., 2002), may link nAChR activation with the JAK/signal transducer and activator of transcription 3 (STAT-3) protective pathway. JAK-2 is also activated by nicotine in non-neuronal cells such as nAChR-bearing keratinocytes (Arredondo et al., 2006). In a microarray study, expression of 8 of 33 JAK/STAT pathway genes was altered when human bronchial epithelial cells were exposed to 5 microM nicotine for 4 to 10 h (Tsai et al., 2006). Thus, the JAK-2/STAT-3 pathway is activated by exposure to nicotine. PubMed:19293145

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act(a(CHEBI:nicotine)) increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Nicotine induced phosphorylation of STAT-3 (signal transducer and activator of transcription 3) in peritoneal macrophages is mediated by an alpha7-dependent activation of JAK-2, as part of the anti-inflammatory action of vagal nerve stimulation (de Jonge et al., 2005). PubMed:19293145

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peritoneal macrophage

act(a(CHEBI:nicotine)) increases p(RGD:Mapk3, pmod(Ph)) View Subject | View Object

Shortterm nicotine application also induces phosphorylation of p44/42MAPK, p38MAPK, and STAT-3 and was mediated mostly by alpha7 nAChRs in rat vascular smooth muscle cells (Wada et al., 2007). It is noteworthy that the JAK-2/STAT-3 pathway also mediates the mitogenic effects of insulin, a process recently implicated in AD (Li and Ho¨lscher, 2007). PubMed:19293145

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vascular associated smooth muscle cell

act(a(CHEBI:nicotine)) increases p(RGD:Mapk14, pmod(Ph)) View Subject | View Object

Shortterm nicotine application also induces phosphorylation of p44/42MAPK, p38MAPK, and STAT-3 and was mediated mostly by alpha7 nAChRs in rat vascular smooth muscle cells (Wada et al., 2007). It is noteworthy that the JAK-2/STAT-3 pathway also mediates the mitogenic effects of insulin, a process recently implicated in AD (Li and Ho¨lscher, 2007). PubMed:19293145

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Cell Ontology (CL)
vascular associated smooth muscle cell

act(a(CHEBI:nicotine)) increases p(RGD:Stat3, pmod(Ph)) View Subject | View Object

Shortterm nicotine application also induces phosphorylation of p44/42MAPK, p38MAPK, and STAT-3 and was mediated mostly by alpha7 nAChRs in rat vascular smooth muscle cells (Wada et al., 2007). It is noteworthy that the JAK-2/STAT-3 pathway also mediates the mitogenic effects of insulin, a process recently implicated in AD (Li and Ho¨lscher, 2007). PubMed:19293145

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Cell Ontology (CL)
vascular associated smooth muscle cell

a(CHEBI:nicotine) increases act(g(HGNC:NIN)) View Subject | View Object

Microarray studies have shown that 24-h incubation in nicotine causes the up-regulation of several genes in SH-SY5Y cells, including ninein (Dunckley and Lukas, 2006), which is known on the basis of a yeast two-hybrid screen to interact with the AD-implicated gene glycogen synthase kinase 3beta (Hong et al., 2000). PubMed:19293145

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SH-SY5Y

a(CHEBI:nicotine) increases act(g(HGNC:PTGS2)) View Subject | View Object

Application of nicotine to rat microglia results in the up-regulated expression of cyclooxygenase-2 and prostaglandin E2 (De Simone et al., 2005). Signaling pathways downstream to the MAPK pathway are similarly well placed to effect changes in gene expression. For example, alpha7-dependent activation of the MAPK pathway is known to activate c-Myc (Liu et al., 2007), a protooncogene whose transcription product sensitizes cells to pro-apoptotic stimuli. PubMed:19293145

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microglial cell

a(CHEBI:nicotine) increases a(CHEBI:"prostaglandin E1(1-)") View Subject | View Object

Application of nicotine to rat microglia results in the up-regulated expression of cyclooxygenase-2 and prostaglandin E2 (De Simone et al., 2005). Signaling pathways downstream to the MAPK pathway are similarly well placed to effect changes in gene expression. For example, alpha7-dependent activation of the MAPK pathway is known to activate c-Myc (Liu et al., 2007), a protooncogene whose transcription product sensitizes cells to pro-apoptotic stimuli. PubMed:19293145

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microglial cell

a(CHEBI:nicotine) increases bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

Furthermore, nicotinic activation of ERK-1/2 promotes survival of cultured murine spinal cord neurons, and the blocking of ERK-1 prevents nicotine’s antiapoptotic action (Toborek et al., 2007). Likewise, the alpha7-specific agonist A-582941 induces phosphorylation of ERK-1/2 in PC12 cells and in mouse brain, and this is completely blocked by the mitogen-activated protein kinase 1 inhibitor SL327 (Bitner et al., 2007). PubMed:19293145

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a(CHEBI:nicotine) increases bp(GO:"MAPK cascade") View Subject | View Object

Nicotine also activates ERK in non-neuronal cells such as pancreatic acinar cells (Chowdhury et al., 2007) and vascular smooth muscle cells (Kanda and Watanabe, 2007), although it is not known in those cases which nAChR subtypes are involved. In the cortex and hippocampus of mice, nicotine’s inhibition of MAPK (shown by RNAi reduction of alpha7 expression to be alpha7-dependent) prevents activation of nuclear factor- kappaB and c-Myc, also thereby reducing the activity of inducible nitric-oxide synthetase and NO production and decreasing Abeta production (Liu et al., 2007). PubMed:19293145

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pancreatic acinar cell
Cell Ontology (CL)
vascular associated smooth muscle cell

act(a(CHEBI:nicotine)) increases composite(p(FPLX:JAK), p(HGNC:STAT3)) View Subject | View Object

Paradoxically, Abeta also activates the MAPK pathway through an alpha7-dependent pathway (Dineley et al., 2001; Bell et al., 2004). In human oral keratinocytes, the Ras/Raf/mitogen-activated protein kinase kinase 1/ERK pathway cooperates with the nicotine activation of the JAK/STAT-3 pathway (Arredondo et al., 2006); the Ras pathway induces STAT-3 upregulation whereas the JAK/STAT-3 pathway phosphorylates STAT-3. PubMed:19293145

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a(CHEBI:nicotine) decreases act(a(CHEBI:"N-methyl-D-aspartic acid")) View Subject | View Object

There is evidence that nicotine’s neuroprotective effects can be mediated through tumor necrosis factor-alpha (TNF-alpha). Application of either nicotine or TNF-alpha protects cultured mouse embryonic cortical neurons from N-methyl-D-aspartate (NMDA) toxicity, but coapplication of both does not. PubMed:19293145

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a(CHEBI:nicotine) regulates act(p(HGNC:TNF)) View Subject | View Object

Nicotine may regulate the neuroprotective secretion of TNFalpha by microglia through enhancement of lowlevel TNF secretion and suppression of lipopolysaccharide- induced TNFalpha secretion (Suzuki et al., 2006; Park et al., 2007) via alpha7-dependent activation of JNK and MAPK pathways. PubMed:19293145

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a(CHEBI:nicotine) decreases a(MESH:Lipopolysaccharides) View Subject | View Object

Nicotine may regulate the neuroprotective secretion of TNFalpha by microglia through enhancement of lowlevel TNF secretion and suppression of lipopolysaccharide- induced TNFalpha secretion (Suzuki et al., 2006; Park et al., 2007) via alpha7-dependent activation of JNK and MAPK pathways. PubMed:19293145

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a(CHEBI:nicotine) association bp(GO:"calcium-mediated signaling") View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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PC12

a(CHEBI:nicotine) association p(HGNCGENEFAMILY:"Inositol 1,4,5-triphosphate receptors") View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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PC12

a(CHEBI:nicotine) association p(HGNCGENEFAMILY:"Ryanodine receptors") View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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PC12

a(CHEBI:nicotine) association p(FPLX:ERK) View Subject | View Object

Nicotine protects PC12 cells from cell death resulting from serum depletion through a mechanism that depends upon the function of IP3 receptors, L-type calcium channels, ryanodine receptors, and ERK, suggesting that the protective effect of nicotine is mediated by calcium signaling pathways (Ren et al., 2005). PubMed:19293145

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PC12

act(a(CHEBI:nicotine)) association a(MESH:Calcineurin) View Subject | View Object

Stevens et al. (2003) showed that calcineurin is involved in nicotine neuroprotection. Abeta, through alpha7 nAChRs, increases Ca2+, which phosphorylates NMDARs via calcineurin and protein tyrosine phosphatase, nonreceptor type 5 (striatum-enriched) (Snyder et al., 2005). PubMed:19293145

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a(CHEBI:nicotine) increases a(CHEBI:"calcium(2+)") View Subject | View Object

It has been shown that the alpha7 receptors, but not the alpha3beta2 receptors, specifically trigger calcium release from intracellular stores by activating ryanodine receptors. Such a specific functional coupling of alpha7 receptors and ryanodine-sensitive stores may provide another site of therapeutic intervention. However, the sustained calcium rise seen in these cells upon prolonged nicotine administration, which is more likely to be of relevance to neuroprotection than short-term responses, is more dependent upon the activation of inositol 1,4,5-triphosphate receptors (Dajas-Bailador et al., 2002a), which are also a target for phosphorylation by FYN (Cui et al., 2004). PubMed:19293145

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a(CHEBI:nicotine) increases sec(a(HBP:"sAPP-beta")) View Subject | View Object

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145

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PC12

a(CHEBI:nicotine) decreases a(HBP:"sAPP-gamma") View Subject | View Object

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145

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a(CHEBI:nicotine) increases act(p(FPLX:CHRN)) View Subject | View Object

The nicotine initially activates nAChRs on DA neurons, causing an increase in burst firing and overall firing rate (88, 121, 123, 124, 134). PubMed:17009926

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Cell Ontology (CL)
dopaminergic neuron

a(CHEBI:nicotine) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

Nicotine decreases tonic DA release in the striatum that is evoked by single action potentials (127), and nicotine also alters the frequency dependence of DA release that is electrically evoked by stimulus trains (130, 131). PubMed:17009926

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Cell Ontology (CL)
neuron
MeSH
Corpus Striatum

a(CHEBI:nicotine) increases act(p(HGNC:CHRNA7)) View Subject | View Object

Simultaneously, nicotine activates presynaptic α7∗ nAChRs, boosting glutamatergic synaptic transmission onto DA neurons (23, 88, 123, 134). PubMed:17009926

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MeSH
Presynaptic Terminals

a(CHEBI:nicotine) increases bp(GO:memory) View Subject | View Object

In animal studies, acute and chronic nicotine administration improves working memory, and nicotinic agonists were found to improve learning and memory in humans and nonhuman primates (145). PubMed:17009926

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a(CHEBI:nicotine) increases bp(GO:"circadian sleep/wake cycle, wakefulness") View Subject | View Object

Moreover, although nicotine increases wakefulness in wild-type mice, it does not affect β2−/− mice. Overall, stimulation of nAChRs promotes arousal and REM sleep. PubMed:17009926

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MeSH
Epilepsy

a(CHEBI:nicotine) increases act(p(HGNC:CHRNA7)) View Subject | View Object

Those that contain β 2 ( β 2 * ) commonly have high affinity for nicotine, desensitize to low agonist con- centrations, have relatively slow kinetics, and do not bind α -bungarotoxin. PubMed:26472524

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a(CHEBI:nicotine) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Similarly, nicotine can mimic the ACh effects on the HPA axis by activating nicotinic receptors PubMed:26813123

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a(CHEBI:nicotine) decreases bp(GO:"apoptotic process") View Subject | View Object

Akt phosphorylation mediates the downstream activation of an antiapoptotic pathway, which is also activated by nicotine treatment (Kihara et al., 2001) PubMed:25514383

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a(CHEBI:nicotine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

The analysis of the Abeta fraction reduced by nicotine showed that mainly insoluble Ab1-40/42 was affected while there was no change in soluble Abeta (Nordberg et al., 2002) PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

The short-term treatment of 10 days showed a significant reduction in cortical insoluble Abeta1-40/42 PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

The analysis of the Abeta fraction reduced by nicotine showed that mainly insoluble Ab1-40/42 was affected while there was no change in soluble Abeta (Nordberg et al., 2002) PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

The short-term treatment of 10 days showed a significant reduction in cortical insoluble Abeta1-40/42 PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Long-term nicotine administration elicited a reduction in Abeta deposits in blood vessel PubMed:25514383

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MeSH
Blood Vessels
MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

APPSwe mice at 14.5 months have fewer alphaBungarotoxin binding sites, while in transgenic mice treated with nicotine the number of alphaBungarotoxin binding sites was recovered and comparable to non transgenic age-matched control mice, suggesting that there was an increase in the population of alpha7 nAChRs (Hellstrom-Lindahl et al., 2004) PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013) PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

Nicotine treatment improved the memory deficit, highlighted with the Morris water maze task. Surprisingly, this study showed a dose dependent increase of alpha7 nAChR, a result that is in contrast with the literature (Oddo et al., 2005) PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases path(MESH:"Memory, Episodic") View Subject | View Object

Mice aged 6 months were treated for one month with nicotine injections, which led to an improvement in working and episodic memory compared to non-treated transgenic mice PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases path(MESH:"Spatial Memory") View Subject | View Object

Like the young mice, they also displayed an improvement in spatial memory, demonstrating that nicotine enhances memory in both young and old mice PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases a(HBP:"amyloid-beta oligomers") View Subject | View Object

The amount of Abeta was quantified, and following nicotine injections a reduction in Abeta, particularly in the oligomeric form, was found PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases a(HBP:"Tau aggregates") View Subject | View Object

The long-term nicotine treatment caused faster tau aggregation in CA1 pyramidal neurons PubMed:25514383

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MeSH
CA1 Region, Hippocampal
MeSH
Pyramidal Cells
MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases a(HBP:"Tau aggregates") View Subject | View Object

The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases bp(GO:"p38MAPK cascade") View Subject | View Object

The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Even though nicotine showed a positive effect reducing plaque load (Hellstrom-Lindahl et al., 2004; Inestrosa et al., 2013; Nordberg et al., 2002), its use in AD treatment should be limited due to its toxic effect on tau pathology PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases bp(GO:memory) View Subject | View Object

Nicotine treatment improved the memory deficit, highlighted with the Morris water maze task. Surprisingly, this study showed a dose dependent increase of alpha7 nAChR, a result that is in contrast with the literature (Oddo et al., 2005) PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Wild-type mice treated with nicotine or with SSR180711, another partial agonist of alpha7 (Biton et al., 2006), showed increased LTP, while the transgenic AD model APPSwe/PS1DE9 showed no effect on LTP following SSR180711 treatment PubMed:25514383

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) regulates p(FPLX:CHRN) View Subject | View Object

nAChRs also underlie the behavioral and addictive properties of nicotine PubMed:28445721

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a(CHEBI:nicotine) increases surf(p(HBP:HBP00174)) View Subject | View Object

Numerous studies have shown that chronic nicotine exposure enhances surface expression of nAChRs, especially for the alpha4beta2 subtype (Schwartz and Kellar, 1983) PubMed:28445721

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a(CHEBI:nicotine) increases a(HBP:HBP00174) View Subject | View Object

We found that nicotine exposure does not affect alpha7 in absence and presence of NACHO (Figures S1C and S1D), and nicotine markedly enhanced alpha4beta2 surface in a manner additive with NACHO (Figures 3G and 3H) PubMed:28445721

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a(CHEBI:nicotine) increases complex(p(HGNC:CHRNA4), p(HGNC:CHRNA4), p(HGNC:CHRNB2), p(HGNC:CHRNB2), p(HGNC:CHRNB2)) View Subject | View Object

A major subtype in the brain is alpha4beta2; the (alpha42beta23) stoichiometry exhibits at least 10-fold-higher sensitivity than (alpha43beta22), so that only the former has the high sensitivity (HS) that allows activation at nicotine concentrations in the 0.1–1 mM range, produced by moderate tobacco use and by the various nicotine replacement therapies PubMed:21482353

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MeSH
Brain

a(CHEBI:nicotine) increases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

alpha7 nAChRs also respond to nicotine concentrations roughly an order of magnitude higher than alpha42beta23, and alpha7 nAChRs have high Ca2+ permeability resembling that of NMDA receptors PubMed:21482353

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a(CHEBI:nicotine) increases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

While it is not yet possible to know precisely how well a7 nAChRs are activated by smoked nicotine, one can reasonably hypothesize that the patients’ higher dose of nicotine activates alpha7 nAChRs (Adler et al., 1993; Papke and Thinschmidt, 1998; Royal College of Physicians, 2007) PubMed:21482353

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MeSH
Schizophrenia

a(CHEBI:nicotine) increases act(p(MGI:Lynx1)) View Subject | View Object

Evidence thus far indicates that the lynx family is regulated in response to relatively strong perturbations: downregulation in NKCC1 knockout mice (Pfeffer et al., 2009), in adenylyl cyclase mutant mice (Wieczorek et al., 2010), and by alpha7 nAChR blockade (Hruska et al., 2009), whereas it is upregulated at the close of the critical period in the visual cortex, and by nicotine in the lung (Sekhon et al., 2005) PubMed:21482353

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MeSH
Lung

a(CHEBI:nicotine) increases act(p(FPLX:CHRN)) View Subject | View Object

Nicotine both activates and desensitizes nAChRs in midbrain dopaminergic neurons (Brodie, 1991; Pidoplichko et al., 1997), and the pleasurable effects associated with nicotine intake occur in large part via the mesolimbic dopaminergic reward system (Corrigall et al., 1992; Koob and Volkow,2010) PubMed:21482353

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MeSH
Dopaminergic Neurons

a(CHEBI:nicotine) increases p(FPLX:CHRN) View Subject | View Object

At the level of whole brain, chronic nicotine causes selective upregulation of nAChRs among major brain regions. Upregulation occurs in cortex, midbrain, and hypothalamus, but not in thalamus or cerebellum (Pauly et al., 1991; Marks et al., 1992; Nguyen et al., 2003; Nashmi et al., 2007; Doura et al., 2008) PubMed:21482353

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MeSH
Cerebral Cortex
MeSH
Hypothalamus
MeSH
Mesencephalon

a(CHEBI:nicotine) causesNoChange p(FPLX:CHRN) View Subject | View Object

At the level of whole brain, chronic nicotine causes selective upregulation of nAChRs among major brain regions. Upregulation occurs in cortex, midbrain, and hypothalamus, but not in thalamus or cerebellum (Pauly et al., 1991; Marks et al., 1992; Nguyen et al., 2003; Nashmi et al., 2007; Doura et al., 2008) PubMed:21482353

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MeSH
Cerebellum
MeSH
Thalamus

a(CHEBI:nicotine) increases bp(GO:cognition) View Subject | View Object

However, it is not known whether the nicotine-enhanced cognitive performance exceeds the level that would occur if the person had never begun to smoke, or after remaining abstinent for one year (the usual criterion for successful smoking cessation) (Levin et al., 2006) PubMed:21482353

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a(CHEBI:nicotine) increases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Chronic or acute nicotine enhances LTP in several regions of hippocampus, especially dentate gyrus (Nashmi et al., 2007; TangandDani, 2009;Pentonet al., 2011) PubMed:21482353

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MeSH
Dentate Gyrus
MeSH
Hippocampus

a(CHEBI:nicotine) decreases a(CHEBI:dopamine) View Subject | View Object

For instance, dopamine increases in the extended amygdala during stress, fear, and nicotine withdrawal (Inglis and Moghaddam, 1999; Pape, 2005; Grace et al., 2007; Gallagher et al., 2008; Koob, 2009; Marcinkiewcz et al., 2009) PubMed:21482353

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MeSH
Amygdala

a(CHEBI:nicotine) increases tloc(a(CHEBI:dopamine), fromLoc(MESH:"Presynaptic Terminals"), toLoc(GO:"extracellular region")) View Subject | View Object

Chronic nicotine upregulates alpha4* nAChRs in dopaminergic presynaptic terminals, apparently leading to increased resting dopamine release from those terminals PubMed:21482353

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MeSH
Dopaminergic Neurons
MeSH
Presynaptic Terminals

a(CHEBI:nicotine) increases act(a(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

In the medial perforant path, which mainly arises from layer II stellate cells, chronic nicotine upregulates alpha4beta2* nAChRs PubMed:21482353

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Annotations
MeSH
Dentate Gyrus
MeSH
Entorhinal Cortex

a(CHEBI:nicotine) increases act(a(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

In midbrain, chronic nicotine treatment elicits a general increase in alpha4beta2* nAChRs in GABAergic neurons, but only in axon terminals of DA neurons PubMed:21482353

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MeSH
GABAergic Neurons
MeSH
Mesencephalon

a(CHEBI:nicotine) increases act(a(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

Because alpha4beta2 nAChRs are the most susceptible to nicotine-induced upregulation, the data again seem consistent with the idea that selective upregulation of alpha4beta2 nAChRs underlies nicotine dependence PubMed:21482353

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a(CHEBI:nicotine) increases act(a(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

The upregulation of alpha4beta2* nAChRs by chronic nicotine treatment has been replicated many times in numerous systems—transfected cell lines, neurons in culture, brain slices, and smokers’ brains (Albuquerque et al., 2009; Fu et al., 2009; Lester et al., 2009; Srinivasan et al., 2011 PubMed:21482353

Appears in Networks:

a(CHEBI:nicotine) increases act(a(HBP:"alpha-4 beta-2 nAChR")) View Subject | View Object

(3) Nicotine activates alpha4beta2 nAChRs ~400-fold more effectively than it activates muscle-type nAChRs, because of cation-π and H-bond interactions at the agonist binding site (Xiu et al., 2009) PubMed:21482353

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a(CHEBI:nicotine) causesNoChange a(HBP:"alpha-4-containing nAChR") View Subject | View Object

While chronic nicotine does not change the abundance or function of alpha4* nAChRs in the somata of substantia nigra pars compacta dopaminergic neurons, it does suppress baseline firing rates of these DA neurons. PubMed:21482353

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MeSH
Pars Compacta

a(CHEBI:nicotine) increases act(a(HBP:"alpha-4-containing nAChR")) View Subject | View Object

These contrasting effects on GABA and DA neurons are due to upregulated alpha4* nAChR responses in GABA neurons, at both somata and synaptic terminals PubMed:21482353

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MeSH
GABAergic Neurons

a(CHEBI:nicotine) increases act(a(HBP:"alpha-4-containing nAChR")) View Subject | View Object

Chronic nicotine upregulates alpha4* nAChRs in dopaminergic presynaptic terminals, apparently leading to increased resting dopamine release from those terminals PubMed:21482353

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Presynaptic Terminals

a(CHEBI:nicotine) increases tloc(a(HBP:"alpha-4-containing nAChR"), fromLoc(GO:"endoplasmic reticulum"), toLoc(GO:"extracellular region")) View Subject | View Object

The chaperoning of nAChRs by nicotine enhances the export of alpha4beta2 nAChRs from the endoplasmic reticulum (ER), and this leads to a general increase in ER exit sites (Srinivasan et al., 2011) PubMed:21482353

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a(CHEBI:nicotine) decreases act(a(MESH:"Dopaminergic Neurons")) View Subject | View Object

While chronic nicotine does not change the abundance or function of alpha4* nAChRs in the somata of substantia nigra pars compacta dopaminergic neurons, it does suppress baseline firing rates of these DA neurons. PubMed:21482353

Appears in Networks:
Annotations
MeSH
Pars Compacta

a(CHEBI:nicotine) increases act(a(MESH:"GABAergic Neurons")) View Subject | View Object

In mice exposed to chronic nicotine, GABA neurons in substantia nigra pars reticulata have increased baseline firing rates, both in brain slices and in anesthetized animals PubMed:21482353

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MeSH
Pars Reticulata

a(CHEBI:nicotine) decreases path(HBP:"Autosomal Dominant Nocturnal Frontal Lobe Epilepsy") View Subject | View Object

ADNFLE patients who use a nicotine patch or tobacco have fewer seizures (Willoughby et al., 2003; Brodtkorb and Picard, 2006) PubMed:21482353

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a(CHEBI:nicotine) increases bp(GO:memory) View Subject | View Object

The potential therapeutic benefit of nAChR stimulation in AD is based upon the fact that nicotine improves memory in animals, healthy subjects, and AD patients (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Rusted and Warburton 1992) PubMed:11230871

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases bp(GO:memory) View Subject | View Object

Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992) PubMed:11230871

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases bp(GO:learning) View Subject | View Object

Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992) PubMed:11230871

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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases path(MESH:Attention) View Subject | View Object

Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992) PubMed:11230871

Appears in Networks:
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MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

Chronic exposure to nicotine causes a striking increase, typically by twofold, in the total number of high-affinity receptors — a process termed upregulation8. PubMed:19721446

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Text Location
Review

act(a(CHEBI:nicotine)) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Regardless of the exact effect of Abeta1–42 on receptor activity, it does seem to block the activation by nicotine and, consistent with the cytoprotective nature of this interaction, amyloid deposition limits neuroprotection151. This phenomenon may explain at least part of the neurotoxicity that is associated with Abeta1–42 (ReF. 156). PubMed:19721446

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Text Location
Review

a(CHEBI:nicotine) increases bp(GO:cognition) View Subject | View Object

early studies indicated that acute nicotine administration improved performance of patients with Alzheimer’s disease in cognitive tasks, whereas acute administration of the non-competitive (channel blocker) antagonist mecamylamine resulted in dose-dependent impairment of performance in a battery of cognitive tasks137–141 PubMed:19721446

Appears in Networks:
Annotations
MeSH
Alzheimer Disease
Text Location
Review

a(CHEBI:nicotine) association bp(MESH:Neuroprotection) View Subject | View Object

The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151. PubMed:19721446

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Annotations
Experimental Factor Ontology (EFO)
PC12
Text Location
Review

a(CHEBI:nicotine) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123. PubMed:19721446

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MeSH
Alzheimer Disease
Text Location
Review

a(CHEBI:nicotine) increases bp(MESH:"Sensory Gating") View Subject | View Object

Patients with schizophrenia174 and DBA/2 mouse models180,181 respond to nicotine administration with improved sensory gating, presumably through alpha7 nAChR activation182,183. PubMed:19721446

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MeSH
Schizophrenia
Text Location
Review

act(a(CHEBI:nicotine)) association p(HGNC:CHRNB4) View Subject | View Object

Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107 PubMed:19721446

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MeSH
Corpus Striatum
Text Location
Review

act(a(CHEBI:nicotine)) association p(HGNC:CHRNA2) View Subject | View Object

Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107 PubMed:19721446

Appears in Networks:
Annotations
MeSH
Corpus Striatum
Text Location
Review

act(a(CHEBI:nicotine)) association p(HGNC:CHRNA5) View Subject | View Object

Moreover, nAChRs containing β4, α2 and α5 in the habenulo-interpeduncular systems are necessary for nicotine withdrawal in mice107 PubMed:19721446

Appears in Networks:
Annotations
MeSH
Corpus Striatum
Text Location
Review

act(a(CHEBI:nicotine)) decreases path(MESH:Nociception) View Subject | View Object

Also, α7- and non-α7-containing nicotinic receptors directly or indirectly (through GABAergic interneurons) modulate serotonin release in spinal cord slices230. However, the identity of the receptors that are responsible for the spinal control of nociception is currently unknown. in this process, the nicotine-induced antinociception seems to be mediated primarily by activation of calcium– calmodulin-dependent protein kinase 2, but this is not the case for supraspinal nociception control229. PubMed:19721446

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Text Location
Review

a(CHEBI:nicotine) regulates sec(a(CHEBI:dopamine)) View Subject | View Object

Nicotine facilitates dopamine release by acting at both somatodendritic and presynaptic nAChRs on mesolimbic246,247 and nigrostriatal247 neurons. PubMed:19721446

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Text Location
Review

a(CHEBI:nicotine) increases a(MESH:"alpha6beta2 nicotinic acetylcholine receptor") View Subject | View Object

After nicotine treat- ment for 24 h at 30µM nicotine, 125 I-labeled epibatidine bind- ing to a6b2 receptors increased significantly at 37 and 30°C. PubMed:18174175

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a(CHEBI:nicotine) increases act(p(FPLX:CHRN)) View Subject | View Object

In terms of functional effects, nicotine acts acutely much in the way that ACh does, causing opening of nAChR channels. PubMed:21787755

Appears in Networks:

a(CHEBI:nicotine) increases act(a(MESH:"SNARE Proteins")) View Subject | View Object

Furthermore, nicotinic stimulation rapidly induced SNARE-dependent vesicular endocytosis accompanied by receptor internalization [166]. However, the number of surface α7 AChRs was not modified since a SNARE-dependent pro- cess also recruited receptors to the cell surface from internal pools (Fig. 5). PubMed:22040696

Appears in Networks:

a(CHEBI:nicotine) increases a(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

This range is broader but similar to what was observed for a4b2 where the -fold increase after nicotine treat- ment varied 3–6-fold (29). PubMed:18174175

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a(CHEBI:nicotine) increases a(HBP:"alpha-3 beta-2 nAChR") View Subject | View Object

At 37°C, the timecourse of the a6b2 and a3b2 up-regulation is essentially complete after 2 h, and no signifi- cant changes were observed with longer nicotine incubations. PubMed:18174175

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a(CHEBI:nicotine) regulates bp(GO:"inflammatory response") View Subject | View Object

Nicotine has been shown to modulate inflammation by affecting STAT3 phosphorylation (Chatterjee et al., 2009; Hosur and Loring, 2011) and by opposing NFkB activation (Leite et al., 2010; Zhou et al., 2010) PubMed:23178521

Appears in Networks:

a(CHEBI:nicotine) association p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Nicotine has been shown to modulate inflammation by affecting STAT3 phosphorylation (Chatterjee et al., 2009; Hosur and Loring, 2011) and by opposing NFkB activation (Leite et al., 2010; Zhou et al., 2010) PubMed:23178521

Appears in Networks:

a(CHEBI:nicotine) decreases act(p(FPLX:NFkappaB)) View Subject | View Object

Nicotine has been shown to modulate inflammation by affecting STAT3 phosphorylation (Chatterjee et al., 2009; Hosur and Loring, 2011) and by opposing NFkB activation (Leite et al., 2010; Zhou et al., 2010) PubMed:23178521

Appears in Networks:

a(CHEBI:nicotine) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:nicotine) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

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Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:nicotine) causesNoChange sec(p(HBP:"sAPP-beta")) View Subject | View Object

Nicotine does not appear to affect sAPPβ and sAPPα secretion in 7W CHO contrary to anatabine (Fig. 4) PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:nicotine) causesNoChange sec(p(HBP:"sAPP-alpha")) View Subject | View Object

Nicotine does not appear to affect sAPPβ and sAPPα secretion in 7W CHO contrary to anatabine (Fig. 4) PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:nicotine) causesNoChange act(complex(GO:"NF-kappaB complex")) View Subject | View Object

We observed that anatabine dose dependently inhibited NFκB activation by TNFα in HEK293 NFκB luciferase reporter cells (Fig. 5) whereas nicotine was ineffective PubMed:21958873

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Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:nicotine) increases act(a(MESH:"Adrenal Glands")) View Subject | View Object

For example, immediately after exposure to nicotine, there is a “stimulant-kick” caused, in part, by its stimulation of the adrenal glands and resultant discharge of epinephrine (adrenaline) PubMed:28391535

Appears in Networks:
Annotations
MeSH
Adrenal Glands

a(CHEBI:nicotine) increases sec(a(CHEBI:adrenaline)) View Subject | View Object

For example, immediately after exposure to nicotine, there is a “stimulant-kick” caused, in part, by its stimulation of the adrenal glands and resultant discharge of epinephrine (adrenaline) PubMed:28391535

Appears in Networks:
Annotations
MeSH
Adrenal Glands

a(CHEBI:nicotine) decreases sec(a(CHEBI:"insulin (human)")) View Subject | View Object

Nicotine also suppresses insulin output from the pancreas, which indicates that smokers are usually hyperglycemic (higher blood sugar level) PubMed:28391535

Appears in Networks:
Annotations
MeSH
Pancreas

a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Centrally, (-)-nicotine has affinity for all brain nAChR subtypes, but binds preferentially and with high affinity to α4β2 nAChRs (e.g., [12, 13]) PubMed:28391535

Appears in Networks:

a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

(-)-Nicotine activates all brain nAChR subtypes, but binds preferentially and with high affinity to α4β2 nAChRs (e.g., [12]) PubMed:28391535

Appears in Networks:

a(CHEBI:nicotine) increases sec(a(CHEBI:dopamine)) View Subject | View Object

Moreover, (-)-nicotine (indirectly) can produce a release of dopamine in brain regions that are thought to control pleasure and motivation; dopamine is thought to underlie the pleasurable sensations experienced by smokers (e.g., [14, 15] but see [16]). PubMed:28391535

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:nicotine) increases act(a(CHEBI:dopamine)) View Subject | View Object

For example, (-)-nicotine may increase dopamine activity at some brain sites such as the nucleus accumbens, an area thought to be important to drugs of abuse (e.g., [14, 101, 102]; but see [16, 103]) PubMed:28391535

Appears in Networks:
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MeSH
Nucleus Accumbens

a(CHEBI:nicotine) negativeCorrelation path(MESH:"Motor Activity") View Subject | View Object

For example, in rodents, administration of low doses of nicotine produced increased motor activity whereas high doses produced decreased motor activity (e.g.,[17, 18]) PubMed:28391535

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a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), a(MESH:"Receptors, Nicotinic")) View Subject | View Object

. It is now well established that nicotine binds to nicotinic acetylcholine receptors (nAChRs) at the cellular level and is the prototype drug used to classify nAChRs PubMed:28391535

Appears in Networks:

a(CHEBI:nicotine) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

(-)-Nicotine activates all brain nAChR subtypes, but binds preferentially and with high affinity to α4β2 nAChRs (e.g., [12]) PubMed:28391535

Appears in Networks:

a(CHEBI:nicotine) causesNoChange act(a(CHEBI:Mecamylamine)) View Subject | View Object

In antagonism tests, (-)-nicotine failed to block the stimulus effects of mecamylamine PubMed:28391535

Appears in Networks:

act(a(CHEBI:nicotine)) negativeCorrelation a(CHEBI:Hexamethonium) View Subject | View Object

. It should be noted that hexamethonium, at relatively low doses, does not block the stimulus effects of (-)-nicotine but when administered at high doses has occasionally been reported to attenuate nicotine-like responding; probably the result of penetration into the CNS of a small proportion of the administered dose of drug (e.g., [35, 38, 64, 106, 146]) PubMed:28391535

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.