Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO

Nicotine exerts its behavioral and additive actions through a family of brain nicotinic acetylcholine receptors (nAChRs). Enhancing alpha 7-type nAChR signaling improves symptoms in Alzheimer's disease and schizophrenia. The pharmaceutical study of alpha 7 receptors is hampered because these receptors do not form their functional pentameric structure in cell lines, and mechanisms that underlie alpha 7 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 alpha 7 receptors. NACHO promotes alpha 7 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 alpha 7 receptor assembly and abolishes alpha 7 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.