A chemogenetic receptor that enhances the magnitude and frequency of glycinergic inhibitory postsynaptic currents without inducing a tonic chloride flux

Islam, Robiul, Zhang, Yan, Xu, Li, Sah, Pankaj, and Lynch, Joseph W. (2017) A chemogenetic receptor that enhances the magnitude and frequency of glycinergic inhibitory postsynaptic currents without inducing a tonic chloride flux. ACS Chemical Neuroscience, 8 (3). pp. 460-467.

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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.

Item ID: 65513
Item Type: Article (Research - C1)
ISSN: 1948-7193
Keywords: Chloride channel, Pharmacogenetic, Chemogenetic, Pain, Gene transfer, Ligand-gated, Glycine receptor
Copyright Information: © 2016 American Chemical Society
Funders: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC)
Projects and Grants: ARC LP120100297, NHMRC APP1058542, NHRMC APP1060707
Date Deposited: 15 Jan 2021 06:21
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310110 Receptors and membrane biology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320902 Cellular nervous system @ 25%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3208 Medical physiology > 320801 Cell physiology @ 25%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 50%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 50%
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