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Zinc‐Dependent Modulation of α2‐ and α3‐Glycine Receptor Subunits by Ethanol
Author(s) -
McCracken Lindsay M.,
Trudell James R.,
McCracken Mandy L.,
Harris R. Adron
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12192
Subject(s) - glycine receptor , glycine , chemistry , protein subunit , zinc , biophysics , strychnine , patch clamp , homomeric , biochemistry , amino acid , receptor , biology , organic chemistry , gene
Background Strychnine‐sensitive glycine receptors ( G ly R s) are expressed throughout the brain and spinal cord and are among the strongly supported protein targets of alcohol. This is based largely on studies of the α1‐subunit; however, α2‐ and α3‐GlyR subunits are as or more abundantly expressed than α1‐GlyRs in multiple forebrain brain areas considered to be important for alcohol‐related behaviors, and uniquely some α3‐GlyRs undergo RNA editing. Nanomolar and low micromolar concentrations of zinc ions potentiate G ly R function, and in addition to zinc's effects on glycine‐activated currents, we have recently shown that physiological concentrations of zinc also enhance the magnitude of ethanol (EtOH)'s effects on α1‐GlyRs. Methods Using 2‐electrode voltage‐clamp electrophysiology in oocytes expressing either α2‐ or α3‐GlyRs, we first tested the hypothesis that the effects of EtOH on α2‐ and α3‐GlyRs would be zinc dependent, as we have previously reported for α1‐GlyRs. Next, we constructed an α3P185L‐mutant G ly R to test whether RNA ‐edited and unedited G ly R s contain differences in EtOH sensitivity. Last, we built a homology model of the α3‐GlyR subunit. Results The effects of EtOH (20 to 200 mM) on both subunits were greater in the presence than in the absence of 500 nM added zinc. The α3P185L‐mutation that corresponds to RNA editing increased sensitivity to glycine and decreased sensitivity to EtOH. Conclusions Our findings provide further evidence that zinc is important for determining the magnitude of EtOH's effects at G ly R s and suggest that by better understanding zinc/EtOH interactions at G ly R s, we may better understand the sites and mechanisms of EtOH action.