MECANISMOS DE ACCION DE LA ANESTESIA GENERAL [Artículo de Revisión]
Villarejo-Díaz, Mario (1985)
RESUMEN: Los mecanismos de acción de la anestesia destacan la interacción hidrofóbica. Muchos de los estudios de los mecanismos de acción mencionan la importancia de la doble capa de lípidos. La solubilidad en lípidos es aparentemente esencial para la actividad, sin embargo, otras interacciones con otros componentes de la membrana son también importantes. Como las propriedades físicas como la solubilidad en los lípidos son gobernadas por fuerzas intermoleculares, estas propiedades, comparadas con la potencia anestésica han sido el foco primario de investigación de los mecanismos físicos de la anestesia y han proporcionado las bases para postular una teoría unitaria de la anestesia que sugiere que todos los anestésicos actuan a través del mismo mecanismo. En este artículo se revisan las principales teorías acerca del mecanismo de acción de la anestesia.
Evidence for a Common Binding Cavity for Three General Anesthetics within the GABA-A Receptor
Andrew Jenkins et al (2001)
ABSTRACT: The GABAA receptor is an important target for a variety of general anesthetics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Specific point mutations in the GABAA receptor selectively abolish regulation by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by anesthetic ethers (Mihic et al., 1997; Krasowski et al., 1998; Koltchine et al., 1999), suggesting the existence of discrete binding sites on the GABAA receptor for these drugs. Using anesthetics of different molecular size (isoflurane > halothane > chloroform) together with complementary mutagenesis of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 Å3. The results of the “cutoff” analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABAA receptor. Moreover, the data support a crucial role for Leu232, Ser270, and Ala291 in the a subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.
Defining the Propofol Binding Site Location on the GABA-A Receptor
Moez Bali e Myles H. Akanas (2003)
ABSTRACT: The GABAA receptor is a target of many general anesthetics. The low affinity of general anesthetics has complicated the search for the location of anesthetic binding sites. Attention has focused on two pairs of residues near the extracellular ends of the M2 and M3 membrane-spanning segments, alfa-1Ser270/beta-2Asn265 (15' M2) and alfa-1Ala291/beta-2Met286 (M3). In the 4-Å resolution acetylcholine receptor structure, the aligned positions are separated by ~10 Å. To determine whether these residues are part of a binding site for propofol, an intravenous anesthetic, we probed propofol’s ability to protect cysteines substituted for these residues from modification by the sulfhydryl-specific reagent p-chloromercuribenzenesulfonate (pCMBS-). pCMBS- reacted with cysteines substituted at the four positions in the absence and presence of GABA. Because propofol binding induces conformational change in the GABAA receptor, we needed to establish a reference state of the receptor to compare reaction rates in the absence and presence of propofol. We compared reaction rates in the presence of GABA with those in the presence of propofol + GABA. The GABA concentration was reduced to give a similar fraction of the maximal GABA current in both conditions. Propofol protected, in a concentration-dependent manner, the cysteine substituted for beta-2Met286 from reaction with pCMBS-. Propofol did not protect the cysteine substituted for the aligned alfa-1 subunit position or the 15' M2 segment Cys mutants in either subunit. We infer that propofol may bind near the extracellular end of the beta subunit M3 segment.
Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5
Kuo-Chen Chou (2004)
ABSTRACT: GABA is the main inhibitory neurotransmitter in the mammalian central nervous system. When GABA binds to the ubiquitous GABA-A receptors on neurons, chloride channels are activated leading to a rapid increase in chloride conductance that depresses excitatory depolarization. The GABA-A receptors are targets for many clinically important drugs, such as the benzodiazepines, general anaesthetics, and barbiturates. All of these drugs enhance the chloride current activated by GABA. Of the GABA-A receptor family, the subtype 2 is critical for the treatment of anxiety spectrum disorders. To avoid unwanted side effects, it is necessary to find highly selective drugs that interact only with subtype 2 but not with the related receptors such as subtypes 1, 3, and 5. To realize such a goal, it is important to have not only the 3D (dimensional) structure of subtype 2 but also the 3D structures of subtypes 1, 3, and 5. In this study, the 3D structures of all the four subtypes of GABA-A receptors have been derived. The computer-modeled heteropentameric structures bear the following features: (1) each of the five subunits in the pentamer has an intrachain disulfide bond, a hallmark of ligand-gated pentameric channels; (2) those residues which are sensitive to the binding of the benzodiazepine site ligands are grouped around the alfa 1;2;3;5/gama 2 interfaces; and (3) those residues which are sensitive to the binding of GABA molecules are grouped around the alfa 1;2;3;5/beta 2 interfaces. All these findings are fully consistent with experimental observations. Meanwhile, for those sensitive or key residues, a close look at their subtle difference among the four subtypes has been provided through a highlighted superposition picture. In addition to providing the atomic coordinates, the predicted structures have further clarified some ambiguities that could not been uniquely determined by the existing experimental data, such as the directionality of the subunit arrangement in the heteropentamers. The 3D models may provide a reasonable structural frame or footing for designing highly selective drugs. The present models might be also useful in understanding the basic mechanism of operation of the GABA-A receptors, stimulating novel strategies for developing more specific drugs and better treatments.
