title: A Chemogenetic Receptor That Enhances the Magnitude and Frequency of Glycinergic Inhibitory Postsynaptic Currents without Inducing a Tonic Chloride Flux.
abstract: The gene transfer-mediated expression of inhibitory ion channels in nociceptive neurons holds promise for treating intractable pain. Chemogenetics, which involves expressing constructs activated by biologically inert molecules, is of particular interest as it permits tunable neuromodulation. However, current chloride-permeable chemogenetic constructs are problematic as they mediate a tonic chloride influx which over time would deplete the chloride electrochemical gradient and reduce inhibitory efficacy. Inflammatory pain sensitization can be caused by prostaglandin E2-mediated inhibition of glycinergic inhibitory postsynaptic currents in spinal nociceptive neurons. We developed a highly conducting (100 pS) inhibitory chemogenetic construct based on a human glycine receptor (α1Y279F,A288G) with high ivermectin sensitivity. When virally infected into spinal neurons, 10 nM ivermectin increased the magnitude and frequency of glycinergic postsynaptic currents without activating a tonic chloride flux. The construct should thus produce analgesia. Its human origin and the well-established biocompatibility of its ligand suggest it may be suited to human use.
authors.affiliation: Queensland Brain Institute and ‡School of Biomedical Sciences, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Robiul
authors.initials: R
authors.lastname: Islam
authors.affiliation: Queensland Brain Institute and ‡School of Biomedical Sciences, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Queensland Brain Institute and ‡School of Biomedical Sciences, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Queensland Brain Institute and ‡School of Biomedical Sciences, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sah
authors.affiliation: Queensland Brain Institute and ‡School of Biomedical Sciences, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Joseph W
authors.identifier: 0000-0002-1227-2252
authors.initials: JW
authors.lastname: Lynch
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D007306:Insecticides / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000235:genetics*; D014162:Transfection
chemical_list: D002712:Chlorides; D018756:GABA Antagonists; D005998:Glycine; D049452:Green Fluorescent Proteins; D007306:Insecticides; D010852:Picrotoxin; D018009:Receptors, Glycine; C485184:enhanced green fluorescent protein
keywords: Chloride channel; chemogenetic; gene transfer; glycine receptor; ligand-gated; pain; pharmacogenetic