Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO

Shenyan Gu; Jose A Matta; Brian Lord; Anthony W Harrington; Steven W Sutton; Weston B Davini; David S Bredt

doi:10.1016/j.neuron.2016.01.018

Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO

Neuron. 2016 Mar 2;89(5):948-55. doi: 10.1016/j.neuron.2016.01.018. Epub 2016 Feb 11.

Authors

Shenyan Gu¹, Jose A Matta¹, Brian Lord¹, Anthony W Harrington¹, Steven W Sutton¹, Weston B Davini¹, David S Bredt²

Affiliations

¹ Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
² Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA. Electronic address: dbredt@its.jnj.com.

PMID: 26875622
DOI: 10.1016/j.neuron.2016.01.018

Abstract

Nicotine exerts its behavioral and additive actions through a family of brain nicotinic acetylcholine receptors (nAChRs). Enhancing α7-type nAChR signaling improves symptoms in Alzheimer's disease and schizophrenia. The pharmaceutical study of α7 receptors is hampered because these receptors do not form their functional pentameric structure in cell lines, and mechanisms that underlie α7 receptor assembly in neurons are not understood. Here, a genomic screening strategy solves this long-standing puzzle and identifies NACHO, a transmembrane protein of neuronal endoplasmic reticulum that mediates assembly of α7 receptors. NACHO promotes α7 protein folding, maturation through the Golgi complex, and expression at the cell surface. Knockdown of NACHO in cultured hippocampal neurons or knockout of NACHO in mice selectively and completely disrupts α7 receptor assembly and abolishes α7 channel function. This work identifies NACHO as an essential, client-specific chaperone for nAChRs and has implications for physiology and disease associated with these widely distributed neurotransmitter receptors.

MeSH terms

Acetylcholine / pharmacology
Action Potentials / drug effects
Action Potentials / genetics
Animals
Calnexin / metabolism
Glial Fibrillary Acidic Protein / genetics
Glial Fibrillary Acidic Protein / metabolism
Glutamic Acid / pharmacology
HEK293 Cells
Hippocampus / cytology
Hippocampus / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Isoxazoles / pharmacology
Male
Membrane Proteins / drug effects
Membrane Proteins / metabolism
Mice
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Neurons / drug effects
Neurons / physiology*
Phenylurea Compounds / pharmacology
Protein Subunits / genetics
Protein Subunits / metabolism*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Serotonin / pharmacology
alpha7 Nicotinic Acetylcholine Receptor / genetics
alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea
Glial Fibrillary Acidic Protein
Intracellular Signaling Peptides and Proteins
Isoxazoles
MAP2 protein, human
Membrane Proteins
Microtubule-Associated Proteins
Phenylurea Compounds
Protein Subunits
RIC3 protein, human
RNA, Small Interfering
alpha7 Nicotinic Acetylcholine Receptor
Calnexin
Serotonin
Glutamic Acid
Acetylcholine