Ligand‐Gated Ion Channels

University College London, London, UK
DOI: 10.1038/npg.els.0000154 In book: eLS
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    ABSTRACT: 5-(Trifluoromethyl)-6-(1-methyl-azepan-4-yl)methyl-1H-quinolin-2-one (TMAQ) is a novel nicotinic acetylcholine receptor (nAChR) agonist with strong selectivity for beta4-containing receptors. TMAQ also exhibits remarkable species selectivity, being a potent agonist of nAChRs containing the human beta4 subunit but having no detectable agonist activity on nAChRs containing the rat beta4 subunit. With the aim of identifying subunit domains and individual amino acids, which contribute to the species selectivity of TMAQ, a series of chimeric and mutated beta4 subunits has been constructed. Recombinant receptors containing wild-type, chimeric, or mutated beta4 subunits have been examined by radioligand binding, intracellular calcium assays, and electrophysiological recording. Two adjacent amino acids located within the extracellular loop D domain of the beta4 subunit (amino acids 55 and 56) have been identified as playing a critical role in determining the agonist potency of TMAQ. Mutagenesis of these two residues within the rat beta4 subunit to the corresponding amino acids in the human beta4 subunit (S55N and I56V mutations) confers sensitivity to TMAQ. The converse mutations in the human beta4 subunit (N55S and V56I) largely abolish sensitivity to TMAQ. In contrast, these mutations have little or no effect on sensitivity to the nonselective nicotinic agonist epibatidine. Despite acting as a potent agonist of human beta4-containing nAChRs, TMAQ acts as an antagonist of rat beta4-containing receptors. Our experimental data, together with homology models of the rat and human alpha3beta4 nAChRs, suggest that amino acids 55 and 56 may be involved in the coupling of agonist binding and channel gating.
    Molecular Pharmacology 03/2007; 71(2):389-97. DOI:10.1124/mol.106.030809 · 4.13 Impact Factor
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are members of an extensive super-family of neurotransmitter-gated ion channels. In humans, nAChRs are expressed within the nervous system and at the neuromuscular junction and are important targets for pharmaceutical drug discovery. They are also the site of action for neuroactive pesticides in insects and other invertebrates. Nicotinic receptors are complex pentameric transmembrane proteins which are assembled from a large family of subunits; seventeen nAChR subunits (alpha1-alpha10, beta1-beta4, gamma, delta and epsilon) have been identified in vertebrate species. This review will discuss nAChR subunit diversity and factors influencing receptor assembly and trafficking.
    Molecular Membrane Biology 06/2008; 25(4):279-92. DOI:10.1080/09687680802035675 · 1.69 Impact Factor
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    ABSTRACT: The soft matter of biological systems consists of mesoscopic length scale building blocks, composed of a variety of different types of biological molecules. Most single biological molecules are so small that 1 billion would fit on the full-stop at the end of this sentence, but collectively they carry out the vital activities in living cells whose length scale is at least three orders of magnitude greater. Typically, the number of molecules involved in any given cellular process at any one time is relatively small, and so real physiological events may often be dominated by stochastics and fluctuation behaviour at levels comparable to thermal noise, and are generally heterogeneous in nature. This challenging combination of heterogeneity and stochasticity is best investigated experimentally at the level of single molecules, as opposed to more conventional bulk ensemble-average techniques. In recent years, the use of such molecular experimental approaches has become significantly more widespread in research laboratories around the world. In this review we discuss recent experimental approaches in biological physics which can be applied to investigate the living component of soft condensed matter to a precision of a single molecule.
    Journal of Physics Condensed Matter 11/2011; 23(50):503101. DOI:10.1088/0953-8984/23/50/503101 · 2.35 Impact Factor

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