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: 460-467. doi:10.1021/acschemneuro.6b00382


Author Islam, Robiul
Zhang, Yan
Xu, Li
Sah, Pankaj
Lynch, Joseph W.
Title A chemogenetic receptor that enhances the magnitude and frequency of glycinergic inhibitory postsynaptic currents without inducing a tonic chloride flux
Journal name ACS Chemical Neuroscience   Check publisher's open access policy
ISSN 1948-7193
Publication date 2017-03-15
Sub-type Letter to editor, brief commentary or brief communication
DOI 10.1021/acschemneuro.6b00382
Open Access Status Not yet assessed
Volume 8
Issue 3
Start page 460
End page 467
Total pages 8
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2018
Language eng
Formatted 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.
Keyword Chloride channel
Chemogenetic
Gene transfer
Glycine receptor
Ligand-gated
Pain
Pharmacogenetic
Q-Index Code CX
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Letter to editor, brief commentary or brief communication
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
School of Biomedical Sciences Publications
 
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Created: Mon, 20 Mar 2017, 14:31:18 EST by Kirstie Asmussen on behalf of School of Music