TY - JOUR
T1 - NACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the α4β2 acetylcholine receptor
AU - Mazzaferro, Simone
AU - Whiteman, Sara T.
AU - Alcaino, Constanza
AU - Beyder, Arthur
AU - Sine, Steven M.
N1 - Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Chaperones
KW - Ligand-gated ion channels
KW - Neurotransmitters
KW - Nicotine addiction
UR - http://www.scopus.com/inward/record.url?scp=85087962740&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087962740&partnerID=8YFLogxK
U2 - 10.1007/s00018-020-03592-x
DO - 10.1007/s00018-020-03592-x
M3 - Article
C2 - 32676916
AN - SCOPUS:85087962740
SN - 1420-682X
VL - 78
SP - 1565
EP - 1575
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 4
ER -