title: Phosphorylation mediated structural and functional changes in pentameric ligand-gated ion channels: implications for drug discovery.
abstract: Pentameric ligand-gated ion channels (pLGICs) mediate numerous physiological processes, including fast neurotransmission in the brain. They are targeted by a large number of clinically-important drugs and disruptions to their function are associated with many neurological disorders. The phosphorylation of pLGICs can result in a wide range of functional consequences. Indeed, many neurological disorders result from pLGIC phosphorylation. For example, chronic pain is caused by the protein kinase A-mediated phosphorylation of α3 glycine receptors and nicotine addiction is mediated by the phosphorylation of α4- or α7-containing nicotinic receptors. A recent study demonstrated that phosphorylation can induce a global conformational change in a pLGIC that propagates to the neurotransmitter-binding site. Here we present evidence that phosphorylation-induced global conformational changes may be a universal phenomenon in pLGICs. This raises the possibility of designing drugs to specifically treat disease-modified pLGICs. This review summarizes some of the opportunities available in this area.
authors.affiliation: Queensland Brain Institute, The University of Queensland, St Lucia 4072, Australia.
authors.forename: Sahil
authors.initials: S
authors.lastname: Talwar
authors.affiliation: Queensland Brain Institute, The University of Queensland, St Lucia 4072, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia 4072, Australia. Electronic address: j.lynch@uq.edu.au.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lynch
mesh_terms: D001921:Brain / Q000378:metabolism*; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000737:chemistry / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission
chemical_list: D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D058446:Ligand-Gated Ion Channels; D018009:Receptors, Glycine; D011978:Receptors, Nicotinic
keywords: Conformational changes; Cys-loop receptor; Drug discovery; Pentameric ligand-gated ion channel; Phosphorylation