| The Basic Property of K385 is Important for Potentiation of the Human α1 Glycine Receptor by Ethanol. | |
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MedLine Citation:
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PMID: 22040678 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Ethanol alters the function of several members of the Cys-loop ligand-gated ion channel superfamily (LGIC). Recent studies have shown that the sensitivity of the α1 glycine receptor (GlyR) to ethanol can be affected by the state of G protein activation mediated by interaction of Gβγ with intracellular amino acids in the GlyR. Here we evaluated the physicochemical property of K385 that contributes to ethanol modulation using mutagenesis, patch clamp and biochemical techniques. A conserved substitution (K385R) did not affect either the apparent glycine EC50 (40±1 vs 41±0.5 µM) or the ethanol-induced potentiation (53±5% vs 46±5%) of the human α1 GlyR. On the other hand, replacement of this residue with glutamic acid (K385E), an acidic amino acid, reduced the potentiation of the GlyR to 10±1%. Furthermore, mutations with a hydrophobic leucine (K385L), a hydrogen bond donor glutamine (K385Q) or a neutral residue (K385A) also reduced the ethanol modulation. Lastly, substitution by a large and hydrophobic residue (K385F) and deletion of 385 (K385_) reduced ethanol modulation to 10±4% and 17±0.4%, respectively. Experiments using dynamic cysteine substitution with a methanethiosulfonate (MTS) reagent and homology modeling indicate that the basic property and the position of K385, probably due to its interaction with Gβγ, is critical for ethanol potentiation of the receptor. |
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Authors:
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Patricio A Castro; Maximiliano Figueroa; Gonzalo E Yevenes; Loreto S San Martin; Luis G Aguayo |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-31 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: - ISSN: 1521-0103 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-11-1 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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University of Concepcion. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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