Receptores GABA-A como dianas moleculares de los anestésicos generales: identificación de los sitios de unión provee pistas para la modulación alostérica.

Receptores GABA-A como dianas moleculares de los anestésicos generales: identificación de los sitios de unión provee pistas para la modulación alostérica. GABA A receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation Richard W. Olsen, PhD, Guo-Dong Li, MD, PhD Can J Anesth/J Can Anesth (2011) 58:206-215.   DOI 10.1007/s12630-010-9429-7 Abstract Purpose The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of c-aminobutyric acid type A receptors (GABAA-Rs) in the mechanisms of general anesthesia. Principal findings With the knowledge that all general anesthetics positively modulate GABAA-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABAA-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrana domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, R(?) etomidate, we identified two transmembrana amino acids that were affinity labelled in purified bovine brain GABAA-R. Homology protein structural modelling positions these two residues, aM1-11' and bM3-4', close to each other in a single type of intersubunit etomidato binding pocket at the b/a interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue a/bM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and a/bM1-(-2') is coupled to action of intravenous agents. Conclusions Establishment of a coherent and consistent structural model of the GABAA-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GABAA-R residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs. http://www.springerlink.com/content/541055868n273225/fulltext.pdf

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