A Chemogenetic Receptor That Enhances the Magnitude and Frequency of Glycinergic Inhibitory Postsynaptic Currents without Inducing a Tonic Chloride Flux

Md Islam, Li Xu, Yang Zhang, Pankaj Sah, Joseph W Lynch

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)460-467
Number of pages8
JournalACS Chemical Neuroscience
Volume8
Issue number3
DOIs
Publication statusPublished - 2017
Externally publishedYes

Fingerprint

Inhibitory Postsynaptic Potentials
Chlorides
Fluxes
Neurons
Ivermectin
Nociceptors
Glycine Receptors
Gene transfer
Intractable Pain
Synaptic Potentials
Ion Channels
Biocompatibility
Dinoprostone
Analgesia
Ligands
Pain
Molecules
Genes

Cite this

@article{8a57505399744295aafdcbd5c4758b3c,
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.",
author = "Md Islam and Li Xu and Yang Zhang and Pankaj Sah and Lynch, {Joseph W}",
year = "2017",
doi = "10.1021/acschemneuro.6b00382",
language = "English",
volume = "8",
pages = "460--467",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "3",

}

A Chemogenetic Receptor That Enhances the Magnitude and Frequency of Glycinergic Inhibitory Postsynaptic Currents without Inducing a Tonic Chloride Flux. / Islam, Md; Xu, Li; Zhang, Yang; Sah, Pankaj; Lynch, Joseph W.

In: ACS Chemical Neuroscience, Vol. 8, No. 3, 2017, p. 460-467.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A Chemogenetic Receptor That Enhances the Magnitude and Frequency of Glycinergic Inhibitory Postsynaptic Currents without Inducing a Tonic Chloride Flux

AU - Islam, Md

AU - Xu, Li

AU - Zhang, Yang

AU - Sah, Pankaj

AU - Lynch, Joseph W

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85015147443&partnerID=8YFLogxK

U2 - 10.1021/acschemneuro.6b00382

DO - 10.1021/acschemneuro.6b00382

M3 - Article

VL - 8

SP - 460

EP - 467

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 3

ER -