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PubMed: 28445721

Title
NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain.
Journal
Cell reports
Volume
19
Issue
None
Pages
688-696
Date
2017-04-25
Authors
Matta JA | Gu S | Lord B | Siuda ER | Davini WB | Bredt DS | Harrington AW

Evidence bc4ab1e87a
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nAChRs also underlie the behavioral and addictive properties of nicotine

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

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Evidence 1a8648c255
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Numerous studies have shown that chronic nicotine exposure enhances surface expression of nAChRs, especially for the alpha4beta2 subtype (Schwartz and Kellar, 1983)

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

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Evidence c1ad09436a
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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)

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

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Evidence b693eb4cb4
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At the cellular level, nAChRs can underlie synaptic responses, neuronal excitability, and neurotransmitter release (Dajas-Bailador and Wonnacott, 2004; Gotti and Clementi, 2004; Hogg et al., 2003)

act(a(GO:synapse)) regulates p(FPLX:CHRN) View Subject | View Object

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bp(GO:"neuronal action potential") regulates p(FPLX:CHRN) View Subject | View Object

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bp(GO:"neurotransmitter secretion") regulates p(FPLX:CHRN) View Subject | View Object

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Evidence a39f97af6f
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This NACHO-mediated [3H]epibatidine binding to alpha6beta2 transfectants was also displaced by conotoxin MII (Figure 4E)

a(MESH:"alpha-conotoxin MII") decreases complex(a(CHEBI:epibatidine), a(MESH:"alpha6beta2 nicotinic acetylcholine receptor")) View Subject | View Object

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Evidence d7024191a4
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Homomeric alpha7 receptors are also abundant and are of particular interest as they show very high calcium permeability and are linked to both physiological and disease processes (Gotti and Clementi, 2004; Hogg et al., 2003; Le Nove` re et al., 2002; Lindstrom, 1997; Picciotto, 2003; Role and Berg, 1996

a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") increases bp(GO:"calcium ion transport") View Subject | View Object

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a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") association bp(MESH:"Physiological Phenomena") View Subject | View Object

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a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") association path(MESH:Disease) View Subject | View Object

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bp(MESH:"Physiological Phenomena") association a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

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path(MESH:Disease) association a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

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Evidence 1de1d43a69
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Strikingly, we found that alpha-bungarotoxin did not completely displace [3H]epibatidine binding to alpha7 receptors with NACHO (Figure 3B)

a(MESH:Bungarotoxins) decreases complex(a(CHEBI:epibatidine), a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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Evidence 91f2b2eed3
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General characterization showed that the knockout mice as compared to their wild-type littermates show no changes in body weight, have slight increases in body temperature (Figures S3A and S3B), and exhibit significantly enhanced locomotor activity (Figures S2A and S2B)

bp(GO:"temperature homeostasis") association p(MGI:Tmem35a) View Subject | View Object

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p(MGI:Tmem35a) decreases bp(GO:locomotion) View Subject | View Object

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p(MGI:Tmem35a) association bp(GO:"temperature homeostasis") View Subject | View Object

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Evidence ce17b787f1
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As ACh-gated cation channels, these broadly distributed receptors participate in arousal, motivation, and numerous aspects of cognition (Gotti and Clementi, 2004; Hogg et al., 2003; Le Nove` re et al., 2002; Lindstrom, 1997; Picciotto, 2003; Role and Berg, 1996).

bp(GO:cognition) association p(FPLX:CHRN) View Subject | View Object

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p(FPLX:CHRN) association path(MESH:Arousal) View Subject | View Object

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p(FPLX:CHRN) association path(MESH:Motivation) View Subject | View Object

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p(FPLX:CHRN) association bp(GO:cognition) View Subject | View Object

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path(MESH:Arousal) association p(FPLX:CHRN) View Subject | View Object

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path(MESH:Motivation) association p(FPLX:CHRN) View Subject | View Object

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Evidence a7e8f48826
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Because nAChRs play important roles in cognition (Gotti and Clementi, 2004; Hogg et al., 2003; Le Nove` re et al., 2002; Lindstrom, 1997; Picciotto, 2003; Role and Berg, 1996), we focused attention on this behavi

bp(GO:cognition) association p(FPLX:CHRN) View Subject | View Object

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p(FPLX:CHRN) association bp(GO:cognition) View Subject | View Object

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Evidence 27810ec3b5
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Indeed, presynaptic effects of nAChRs in regulating dopamine release in basal ganglia and prefrontal cortex likely participate in nicotine’s addictive and cognitive effects, respectively (Jasinska et al., 2014)

p(FPLX:CHRN) increases bp(GO:cognition) View Subject | View Object

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p(FPLX:CHRN) increases bp(GO:"dopamine secretion") View Subject | View Object

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Annotations
MeSH
Basal Ganglia
MeSH
Prefrontal Cortex

p(FPLX:CHRN) association path(MESH:"Tobacco Use Disorder") View Subject | View Object

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path(MESH:"Tobacco Use Disorder") association p(FPLX:CHRN) View Subject | View Object

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Evidence 57c54a17cb
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In substantia nigra, postsynaptic nicotinic receptors induce inward currents to excite dopaminergic neurons that project to corpus striatum (Matsubayashi et al., 2003)

act(p(FPLX:CHRN)) increases act(a(MESH:"Dopaminergic Neurons")) View Subject | View Object

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Annotations
MeSH
Substantia Nigra

Evidence 57393fdecc
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Through these postsynaptic effects and by influencing neural excitability, nAChRs can modulate or induce synaptic plasticity (Yakel, 2014)

p(FPLX:CHRN) increases bp(GO:"positive regulation of synaptic plasticity") View Subject | View Object

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Evidence 9a569f6259
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Resistance to inhibitor of cholinesterase-3 (RIC-3) is required for nAChR function in C. elegans (Nguyen et al., 1995)

p(HGNC:RIC3) increases act(p(FPLX:CHRN)) View Subject | View Object

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Evidence 9c49724b98
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Whereas RIC-3 can enhance function of certain mammalian nAChRs, RIC-3 is not essential (Koperniak et al., 2013)

p(HGNC:RIC3) increases act(p(FPLX:CHRN)) View Subject | View Object

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Evidence f42ec786f6
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In C. elegans, RIC-3 protein is essential for nAChR function (Nguyen et al., 1995), and mammalian RIC-3 has modest and mixed effects on nAChRs (Halevi et al., 2003; Millar, 2008)

p(HGNC:RIC3) increases act(p(FPLX:CHRN)) View Subject | View Object

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Evidence e4d0e89c82
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For alpha7 and alpha3beta2, RIC-3 did not enable detectable [3H]epibatidine binding, yet RIC-3 profoundly augmented the effects of NACHO on [3H]epibatidine binding to either receptor subtype (Figures 3A and S1A)

p(HGNC:RIC3) causesNoChange complex(a(CHEBI:epibatidine), a(MESH:"nicotinic receptor alpha3beta2")) View Subject | View Object

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p(HGNC:RIC3) causesNoChange complex(a(CHEBI:epibatidine), a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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Evidence 7dbd7726e0
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As previously reported using fluorescently labeled alpha-bungarotoxin (Gu et al., 2016), NACHO enabled formation of assembled surface alpha7 receptors, and RIC-3 further enhanced this (Figures 3E and 3F)

p(HGNC:RIC3) increases surf(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases surf(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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Evidence 5539ed1118
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Using a genomic cDNA screening strategy, we recently identified NACHO (Gu et al., 2016), a small multi-pass transmembrane protein enriched in neuronal endoplasmic reticulum (ER) that can mediate functional reconstitution of alpha7 receptors in non-neuronal cell lines

p(HGNC:TMEM35A) regulates act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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Evidence 757197a625
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NACHO serves as a molecular chaperone to mediate folding, assembly, and surface expression of alpha7 receptors (Gu et al., 2016)

act(p(HGNC:TMEM35A), ma(chap)) regulates surf(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) regulates a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

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Evidence db7e4b2c2f
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As published previously (Gu et al., 2016), ACh evoked currents from alpha7 require NACHO, and currents from alpha4beta2 were augmented ~3-fold by NACHO, which did not alter the desensitization kinetics of alpha4beta2 receptors (Figures 1A and 1B)

act(p(HGNC:TMEM35A), ma(chap)) increases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases act(a(HBP:HBP00174)) View Subject | View Object

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Evidence cf29b5d130
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As previously published (Gu et al., 2016), robust surface alpha7 and alpha4beta2 expression required co-transfection with NACHO (Figures 1C and D), and we find that alpha3beta2 is also NACHO-dependent (Figures 1C and D)

act(p(HGNC:TMEM35A), ma(chap)) increases surf(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases surf(a(HBP:HBP00174)) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases surf(a(MESH:"nicotinic receptor alpha3beta2")) View Subject | View Object

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Evidence 40e22ac9c5
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Our previous studies demonstrated that NACHO promotes assembly of alpha7 receptors as evidenced by alpha-bungarotoxin labeling, (Gu et al., 2016) which in brain only binds with high affinity to properly folded pentameric alpha7 receptors (Couturier et al., 1990; Schoepfer et al., 1990)

act(p(HGNC:TMEM35A), ma(chap)) increases a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

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Annotations
MeSH
Brain

Evidence f5c4d0493b
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In membranes from alpha7-transfected cells, [3H]epibatidine binding absolutely required NACHO (Figure 2A), which fits with an essential role for NACHO in alpha7 assembly

act(p(HGNC:TMEM35A), ma(chap)) increases a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases complex(a(CHEBI:epibatidine), a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

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Evidence 94460e92c4
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NACHO does not affect function of ion channels gated by numerous other ligands including glutamate, GABA, serotonin, and capsaicin, suggesting that NACHO represents the only essential client-specific chaperone yet identified for any mammalian neurotransmitter receptor (Gu et al., 2016)

p(HGNC:TMEM35A) causesNoChange act(p(FPLX:GABR)) View Subject | View Object

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p(HGNC:TMEM35A) causesNoChange act(a(MESH:"Receptors, Serotonin")) View Subject | View Object

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p(HGNC:TMEM35A) causesNoChange act(p(HGNC:TRPV1)) View Subject | View Object

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p(HGNC:TMEM35A) causesNoChange act(a(MESH:"Receptors, Glutamate")) View Subject | View Object

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Evidence ed718b1b88
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Cells transfected with alpha4beta2 or alpha3beta4 alone showed [3H]epibatidine binding, and this was markedly increased (5- to 10-fold) in presence of NACHO (Figures 2B and 2D)

act(p(HGNC:TMEM35A), ma(chap)) increases a(HBP:HBP00174) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases a(MESH:"nicotinic receptor alpha3beta4") View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases complex(a(CHEBI:epibatidine), a(HBP:HBP00174)) View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases complex(a(CHEBI:epibatidine), a(MESH:"nicotinic receptor alpha3beta4")) View Subject | View Object

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Evidence 53322cee54
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We now also find that alpha3beta2 receptor function in HEK cells requires NACHO, and these channels showed desensitization kinetics generally similar to alpha4beta2 (Figures 1A and 1B)

act(p(HGNC:TMEM35A), ma(chap)) increases act(a(MESH:"nicotinic receptor alpha3beta2")) View Subject | View Object

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Evidence 73c3c74ce7
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Similarly, quantifiable [3H]epibatidine binding to alpha3beta2 required cotransfection with NACHO (Figure 2C)

act(p(HGNC:TMEM35A), ma(chap)) increases a(MESH:"nicotinic receptor alpha3beta2") View Subject | View Object

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act(p(HGNC:TMEM35A), ma(chap)) increases complex(a(CHEBI:epibatidine), a(MESH:"nicotinic receptor alpha3beta2")) View Subject | View Object

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Evidence 0488edcd47
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For alpha3beta4 alone, ACh evoked large slowly-desensitizing responses, and NACHO amplified their magnitudes ~5-fold (Figures 1A and 1B)

act(p(HGNC:TMEM35A), ma(chap)) increases act(a(MESH:"nicotinic receptor alpha3beta4")) View Subject | View Object

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Evidence 3f230dfb46
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For alpha3beta4 alone, we found abundant surface labeling and this was enhanced by NACHO (Figures 1C and 1D)

act(p(HGNC:TMEM35A), ma(chap)) increases surf(a(MESH:"nicotinic receptor alpha3beta4")) View Subject | View Object

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Evidence 97801c7a66
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However, we did find that NACHO enhances [3H]epibatidine binding to cells transfected with alpha6beta2beta3 (Figure 4C) indicating that NACHO can enhance intracellular receptor assembly

p(HGNC:TMEM35A) increases complex(a(CHEBI:epibatidine), a(MESH:"alpha6beta2 nicotinic acetylcholine receptor")) View Subject | View Object

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Evidence 54bfaa3223
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Whereas this subunit combination is not competent to form a functional channel (Champtiaux et al., 2002; Dash et al., 2014; Kuryatov et al., 2000), NACHO still mediated partial receptor assembly as reflected by [3H]epibatidine binding (Figure 4D)

p(HGNC:TMEM35A) increases complex(a(CHEBI:epibatidine), a(MESH:"alpha6beta2 nicotinic acetylcholine receptor")) View Subject | View Object

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p(HGNC:TMEM35A) increases a(MESH:"alpha6beta2 nicotinic acetylcholine receptor") View Subject | View Object

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Evidence a5f3fa9750
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These experiments showed that NACHO is most concentrated in the heavy (P3) and light (P4) microsomal fractions (Figures 3C and 3D), which contain resident endoplasmic reticulum (ER) proteins including calnexin

p(MGI:Canx) association p(MGI:Tmem35a) View Subject | View Object

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p(MGI:Tmem35a) association p(MGI:Canx) View Subject | View Object

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Evidence f221111a71
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Importantly, NACHO knockout mice show complete loss of alpha7 ligand binding and channel function indicating that NACHO is required for formation of alpha7 receptors (Gu et al., 2016)

act(p(MGI:Tmem35a), ma(chap)) increases a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

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Evidence 04d72a07fd
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We previously showed that [125I]alpha-bungarotoxin binding is absent in NACHO knockout mice brain (Gu et al., 2016), which express normal levels of RIC-3 mRNA (Figure S1B)

p(MGI:Tmem35a) increases complex(a(MESH:Bungarotoxins), p(FPLX:CHRN)) View Subject | View Object

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Evidence 31d62b5a3d
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[125I]epibatidine binding was decreased in all brain regions evaluated—it was reduced by 66% in cortex, 39% in striatum, and 51% in medial vestibular nucleus (MVN) (Figures 5A and 5D)

p(MGI:Tmem35a) increases complex(a(CHEBI:epibatidine), a(HBP:HBP00180)) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Corpus Striatum
MeSH
Vestibular Nuclei

Evidence bd7ad258db
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This partial reduction fits with our data showing that NACHO enhances [3H]epibatidine binding to alpha4beta2 and other heteromeric nAChRs but that some [3H]epibatidine binding occurs to certain heteromeric nAChRs in the absence of NACHO (Figure 2B)

p(MGI:Tmem35a) increases complex(a(CHEBI:epibatidine), a(HBP:HBP00174)) View Subject | View Object

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Evidence e885b38e69
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Labeling of alpha6-containing nAChRs in striatum by [125I]conotoxin MII is virtually abolished in NACHO knockout mice (Figures 5B and 5D), indicating a vital role for NACHO in assembly of these presynaptic receptors

p(MGI:Tmem35a) increases a(HBP:HBP00180) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Corpus Striatum

Evidence 26588b339b
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Consistent with our previous autoradiographic results (Gu et al., 2016), we found no detectable [3H]alpha-bungarotoxin binding to brain membranes from NACHO knockouts

p(MGI:Tmem35a) increases complex(a(GO:membrane), a(MESH:Bungarotoxins)) View Subject | View Object

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Annotations
MeSH
Brain

Evidence eaf0d738c1
JSON

In membranes from cerebral cortex, hippocampus, and striatum, we found that levels of [3H]epibatidine binding sites are decreased by 50%–75%

p(MGI:Tmem35a) increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Corpus Striatum
MeSH
Hippocampus

Evidence 13b8abb62f
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A very recent study also reported memory defects in mice lacking NACHO/TMEM35 done by scientists unaware of NACHO’s role in controlling nAChRs (Kennedy et al., 2016)

p(MGI:Tmem35a) regulates p(FPLX:CHRN) View Subject | View Object

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p(MGI:Tmem35a) increases bp(GO:memory) View Subject | View Object

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Evidence 05e1281377
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NACHO knockouts did not show changes in levels of [3H]epibatidine binding to membranes from superior cervical ganglia (wild-type [WT] 329.0 ± 17.2, knockout [KO] 322.8 ± 4.0 fmol/mg protein), which primarily express receptors containing alpha3beta4-containing receptors (David et al., 2010)

p(MGI:Tmem35a) increases a(MESH:"nicotinic receptor alpha3beta4") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Superior Cervical Ganglion

Evidence 575b0b58d8
JSON

The NACHO knockouts showed increased total number of arm entries in the Y-maze, which fits with their enhanced locomotor activity (Figure S2F)

p(MGI:Tmem35a) decreases bp(GO:locomotion) View Subject | View Object

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Evidence fd2a8df7d2
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In the Morris water maze, NACHO knockout mice were delayed in learning the task during acquisition days 1–4 and showed fewer target crossings in the probe test (Figures S2Cand S2D), despite showing no significant difference for genotype on average speed through each acquisition day (ANOVA: F[1,28] = 0.004; p = 0.9492; data not shown)

p(MGI:Tmem35a) increases bp(GO:learning) View Subject | View Object

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Evidence 5607549b23
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NACHO knockout mice also showed deficits of spontaneous alternation in the Y-maze compared to wild-type littermates (Figure S2E)

p(MGI:Tmem35a) increases path(MESH:"Spatial Learning") View Subject | View Object

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p(MGI:Tmem35a) increases path(MESH:"Spatial Memory") View Subject | View Object

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