NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain

Neuronal nicotinic acetylcholine receptors (nAChRs) participate in diverse aspects of brain function and mediate behavioral and addictive properties of nicotine. Neuronal nAChRs derive from combinations of α and β subunits, whose assembly is tightly regulated. NACHO was recently identified as a chaperone for α7-type nAChRs. Here, we find NACHO mediates assembly of all major classes of presynaptic and postsynaptic nAChR tested. NACHO acts at early intracellular stages of nAChR subunit assembly and then synergizes with RIC-3 for receptor surface expression. NACHO knockout mice show profound deficits in binding sites for α-bungarotoxin, epibatidine, and conotoxin MII, illustrating essential roles for NACHO in proper assembly of α7-, α4β2-, and α6-containing nAChRs, respectively. By contrast, GABAA receptors are unaffected consistent with NACHO specifically modulating nAChRs. NACHO knockout mice show abnormalities in locomotor and cognitive behaviors compatible with nAChR deficiency and underscore the importance of this chaperone for physiology and disease associated with nAChRs. [Display omitted] •NACHO protein assembles homomeric and heteromeric nACh receptors•NACHO protein acts in the endoplasmic reticulum to mediate nACh receptor maturation•NACHO knockout mice lack both presynaptic and postsynaptic nACh receptors•NACHO knockout mice show nACh receptor-related behavioral phenotypes Matta et al. find that the NACHO protein is an essential chaperone for the family of nicotinic acetylcholine receptors (nAChRs) throughout the brain. NACHO is present in the endoplasmic reticulum and mediates assembly of both homomeric and heteromeric nAChRs. NACHO knockout mice show behavioral deficits consistent with global loss of nAChRs in brain.