NACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the α4β2 acetylcholine receptor

Simone Mazzaferro, Sara T. Whiteman, Constanza Alcaino, Arthur Beyder, Steven M. Sine

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1565-1575
Number of pages11
JournalCellular and Molecular Life Sciences
Volume78
Issue number4
DOIs
StatePublished - Feb 2021

Keywords

  • Chaperones
  • Ligand-gated ion channels
  • Neurotransmitters
  • Nicotine addiction

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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