Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors

Kasper Harpsøe, Philip K Ahring, Jeppe K Christensen, Marianne L Jensen, Dan Peters, Thomas Balle

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    119 Citations (Scopus)

    Abstract

    The neuronal a4ß2 nicotinic acetylcholine receptors exist as two distinct subtypes, (a4)(2)(ß2)(3) and (a4)(3)(ß2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian a4 and ß2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (a4)(3)(ß2)(2) receptor. In addition to two high-sensitivity sites at a4ß2 interfaces, the (a4)(3)(ß2)(2) receptor contains a third low-sensitivity agonist binding site in the a4a4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three residues, which differ between the a4ß2 and a4a4 sites, control agonist sensitivity. The results presented here provide a basic insight into the function of pentameric ligand-gated ion channels, which enables modulation of the receptors with hitherto unseen precision; it becomes possible to rationally design therapeutics targeting subpopulations of specific receptor subtypes.
    Original languageEnglish
    JournalJournal of Neuroscience
    Volume31
    Issue number30
    Pages (from-to)10759-10766
    ISSN0270-6474
    DOIs
    Publication statusPublished - 27 Jul 2011

    Keywords

    • Former Faculty of Pharmaceutical Sciences

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