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

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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.

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Funding

National Institutes of Health; award number NS31744 to Steven M Sine.

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Authors and Affiliations

  1. Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Simone Mazzaferro, Arthur Beyder & Steven M. Sine

  2. Enteric Neuroscience Program (ENSP), Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA

    Sara T. Whiteman, Constanza Alcaino & Arthur Beyder

  3. Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Steven M. Sine

  4. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Steven M. Sine

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  1. Simone Mazzaferro
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Conceptualization: SM, SMS; Methodology: SM, CA; Formal analysis and investigation: SM, STW and CA; Writing—original draft preparation: SM and SMS; Writing—review and editing: SM, STW, CA, AB and SMS; Funding acquisition: SMS; Resources: AB and SMS; Supervision: SMS.

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Mazzaferro, S., Whiteman, S.T., Alcaino, C. et al. NACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the α4β2 acetylcholine receptor. Cell. Mol. Life Sci. 78, 1565–1575 (2021). https://doi.org/10.1007/s00018-020-03592-x

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