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

Islam, Robiul, Keramidas, A, Xu, Li, Durisic, N, Sah, P, and Lynch, JW (2016) Ivermectin-activated, cation-permeable glycine receptors for the chemogenetic control of neuronal excitation. ACS Chemical Neuroscience, 7 (12). pp. 1647-1657.

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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.

Item ID: 65519
Item Type: Article (Research - C1)
ISSN: 1948-7193
Copyright Information: © 2016 American Chemical Societ
Funders: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC)
Projects and Grants: ARC LP120100297, NHMRC APP1058542, NHMRC APP1060707
Date Deposited: 22 Jul 2021 01:39
FoR Codes: 34 CHEMICAL SCIENCES > 3404 Medicinal and biomolecular chemistry > 340406 Molecular medicine @ 30%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310110 Receptors and membrane biology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320903 Central nervous system @ 20%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 40%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 30%
97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 30%
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