Unraveling the High- and Low-Sensitivity Agonist Responses of Nicotinic Acetylcholine Receptors
Open Access
- 27 July 2011
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 31 (30), 10759-10766
- https://doi.org/10.1523/jneurosci.1509-11.2011
Abstract
The neuronal α4β2 nicotinic acetylcholine receptors exist as two distinct subtypes, (α4)2(β2)3 and (α4)3(β2)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 α4 and β2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (α4)3(β2)2 receptor. In addition to two high-sensitivity sites at α4β2 interfaces, the (α4)3(β2)2 receptor contains a third low-sensitivity agonist binding site in the α4α4 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 α4β2 and α4α4 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.Keywords
This publication has 24 references indexed in Scilit:
- Ongoing and future developments at the Universal Protein ResourceNucleic Acids Research, 2010
- Human α3β4 Neuronal Nicotinic Receptors Show Different Stoichiometry if They Are Expressed in Xenopus Oocytes or Mammalian HEK293 CellsPLOS ONE, 2010
- Pentameric concatenated (α4)2(β2)3 and (α4)3(β2)2 nicotinic acetylcholine receptors: subunit arrangement determines functional expressionBritish Journal of Pharmacology, 2009
- Gene targeting demonstrates that α4 nicotinic acetylcholine receptor subunits contribute to expression of diverse [3H]epibatidine binding sites and components of biphasic 86Rb+ efflux with high and low sensitivity to stimulation by acetylcholineNeuropharmacology, 2007
- Statistical potential for assessment and prediction of protein structuresProtein Science, 2006
- Expresso: automatic incorporation of structural information in multiple sequence alignments using 3D-CoffeeNucleic Acids Research, 2006
- The β Subunit Determines the Ion Selectivity of the GABAA ReceptorPublished by Elsevier BV ,2002
- The Protein Data BankNucleic Acids Research, 2000
- Pharmacological similarities between native brain and heterologously expressed α 4β 2 nicotinic receptorsBritish Journal of Pharmacology, 1999
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993