Ivermectin-activated, cation-permeable glycine receptors for the chemogenetic control of neuronal excitation

Islam, Robiul, Keramidas, Angelo, Xu, Li, Durisic, Nela, Sah, Pankaj and Lynch, Joseph W. (2016) Ivermectin-activated, cation-permeable glycine receptors for the chemogenetic control of neuronal excitation. ACS Chemical Neuroscience, 7 12: 1647-1657. doi:10.1021/acschemneuro.6b00168


Author Islam, Robiul
Keramidas, Angelo
Xu, Li
Durisic, Nela
Sah, Pankaj
Lynch, Joseph W.
Title Ivermectin-activated, cation-permeable glycine receptors for the chemogenetic control of neuronal excitation
Journal name ACS Chemical Neuroscience   Check publisher's open access policy
ISSN 1948-7193
Publication date 2016-12-21
Sub-type Article (original research)
DOI 10.1021/acschemneuro.6b00168
Open Access Status Not yet assessed
Volume 7
Issue 12
Start page 1647
End page 1657
Total pages 11
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2017
Language eng
Formatted abstract
The ability to control neuronal activation is rapidly advancing our understanding of brain function and is widely viewed as having eventual therapeutic application. Although several highly effective optogenetic, optochemical genetic, and chemogenetic techniques have been developed for this purpose, new approaches may provide better solutions for addressing particular questions and would increase the number of neuronal populations that can be controlled independently. An early chemogenetic neuronal silencing method employed a glutamate receptor Cl- channel engineered for activation by 1-3 nM ivermectin. This construct has been validated in vivo. Here, we sought to develop cation-permeable ivermectin-gated receptors that were either maximally Ca2+-permeable so as to induce neuro-excitotoxic cell death or minimally Ca2+-permeable so as to depolarize neurons with minimal excitotoxic risk. Our constructs were based on the human α1 glycine receptor Cl- channel due to its high conductance, human origin, high ivermectin sensitivity (once mutated), and because pore mutations that render it permeable to Na+ alone or Na+ plus Ca2+ are well characterized. We developed a Ca2+-impermeable excitatory receptor by introducing the F207A/P-2′Δ/A-1′E/T13′V/A288G mutations and a Ca2+-permeable excitatory receptor by introducing the F207A/A-1′E/A288G mutations. The latter receptor efficiently induces cell death and strongly depolarizes neurons at nanomolar ivermectin concentrations.
Keyword Chemogenetic
Chloride channel
Excitotoxicity
Glycinergic
Ligand-gated ion channel
Pharmacogenetic
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
School of Biomedical Sciences Publications
 
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