Open AccessNACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the α4β2 acetylcholine receptor
Author(s) -
Simone Mazzaferro,
Sara Whiteman,
Constanza Alcaino,
Arthur Beyder,
Steven M. Sine
Publication year - 2020
Publication title -
cellular and molecular life sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.928
H-Index - 223
eISSN - 1420-9071
pISSN - 1420-682X
DOI - 10.1007/s00018-020-03592-x
Subject(s) - heterologous expression , protein subunit , acetylcholine receptor , allosteric regulation , biophysics , nicotinic agonist , stoichiometry , nicotinic acetylcholine receptor , acetylcholine , chemistry , ion channel , ligand gated ion channel , receptor , biochemistry , biology , microbiology and biotechnology , recombinant dna , pharmacology , organic chemistry , gene
Nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of pentameric ligand-gated ion channels, and in neuronal tissues, are assembled from various types of α- and β-subunits. Furthermore, the subunits α4 and β2 assemble in two predominant stoichiometric forms, (α4) 2 (β2) 3 and (α4) 3 (β2) 2 , forming receptors with dramatically different sensitivity to agonists and allosteric modulators. However, mechanisms by which the two stoichiometric forms are regulated are not known. Here, using heterologous expression in mammalian cells, single-channel patch-clamp electrophysiology, and calcium imaging, we show that the ER-resident protein NACHO selectively promotes the expression of the (α4) 2 (β2) 3 stoichiometry, whereas the cytosolic molecular chaperone 14-3-3η selectively promotes the expression of the (α4) 3 (β2) 2 stoichiometry. Thus, NACHO and 14-3-3η are potential physiological regulators of subunit stoichiometry, and are potential drug targets for re-balancing the stoichiometry in pathological conditions involving α4β2 nAChRs such as nicotine dependence and epilepsy.