EUROPEAN SOCIETY FOR BIOMEDICAL RESEARCH ON ALCOHOLISM. 12â15 SEPTEMBER 2015. VALENCIA, SPAIN. SY17-3. CHARACTERIZATION OF ...
Alcohol and Alcoholism, 2015, 50(S1) i1–i67
Abstracts
ESBRA 2015 EUROPEAN SOCIETY FOR BIOMEDICAL RESEARCH ON ALCOHOLISM 12–15 SEPTEMBER 2015 VALENCIA, SPAIN
SY17-3 CHARACTERIZATION OF ETHANOL SENSITIVE GLYCINE RECEPTORS AND DEVELOPMENT OF ABUSE DISORDERS THERAPY L. G. Aguayo, B. Muñoz, B. Forstera, T. Mariqueo, L. San Martin, and J. L. Guzman Department of Physiology, University of Concepcion, Chile Alcohol affects millions of people worldwide causing great social, medical and economic burdens. Unfortunately, effective pharmacotherapeutic tools are limited, have low adherence and cause several side effects, which emphasizes the need for novel, mechanistically oriented therapies. We found that basic amino acids (316-320 and 385/ 386) regulate the sensitivity of a1 glycine receptors (GlyR) to EtOH. The effects of the mutations are specific for ethanol, since the sensitivity to other positive and negative GlyR modulators were not affected.
Recently, we generated and characterized a Knock In (KI) mouse for the α1 GlyR with mutations in residues 385/386 in the intracellular loop of the receptor. The KI mice had normal behavior and most importantly did not display a hyperexcitable phenotype. Examining spinal and brain stem neurons, we found that GlyRs were less affected by ethanol- and Gγβ− mediated modulations. Interestingly, the mice exhibited a reduced time in Loss of Righting Reflex (LORR) when compared with wild type mice. Searching for inhibitory molecules, we found that a small peptide significantly reduced the ethanol-induced potentiation of GlyR activated currents and miniature inhibitory synaptic currents (mIPSCs). More recently, we found that a small molecule, M554 (an indol derivative), applied intracellularly was able to reduce ethanol potentiation of α1 GlyR. Additionally, i.p. injection of this compound was also able to reduce the LORR in mice. In conclusion, we identified important amino acids that participate in the modulation of GlyRs by ethanol. These findings could lead to the development of new therapy for alcohol related disorders. (Supported by NIH RO1 and Fondecyt grants).
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