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

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 PubMed:28445721

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

NACHO serves as a molecular chaperone to mediate folding, assembly, and surface expression of alpha7 receptors (Gu et al., 2016) PubMed:28445721

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

NACHO serves as a molecular chaperone to mediate folding, assembly, and surface expression of alpha7 receptors (Gu et al., 2016) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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 PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

Similarly, quantifiable [3H]epibatidine binding to alpha3beta2 required cotransfection with NACHO (Figure 2C) PubMed:28445721

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

For alpha3beta4 alone, ACh evoked large slowly-desensitizing responses, and NACHO amplified their magnitudes ~5-fold (Figures 1A and 1B) PubMed:28445721

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

For alpha3beta4 alone, we found abundant surface labeling and this was enhanced by NACHO (Figures 1C and 1D) PubMed:28445721

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

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) PubMed:28445721

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

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 PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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

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 PubMed:28445721

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

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) PubMed:28445721

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

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) PubMed:28445721

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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.