Allosteric Ligands and Their Binding Sites Define y-Aminobutyric Acid ( XXXX ) Type A Receptor Subtypes.

@entity1 @entity1246 @entity4313 @entity7353 @entity1245 @entity5094 @entity4671 @entity2865 @entity1875 @entity1068
UNASSIGNED: GABAA receptors (GABAARs) mediate rapid inhibitory transmission in the brain. GABAARs are ligand-gated @entity2865 ion channel proteins and exist in about a dozen or more heteropentameric subtypes exhibiting variable age and brain regional localization and thus participation in differing brain functions and diseases. GABAARs are also subject to modulation by several chemotypes of allosteric ligands that help define structure and function, including subtype definition. The channel blocker @entity5094 identified a noncompetitive channel blocker site in GABAARs. This ligand site is located in the transmembrane channel pore, whereas the @entity1246 agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Two classes of pharmacologically important allosteric modulatory ligand binding sites reside in the extracellular domain at modified agonist sites at other subunit interfaces: the @entity1245 site and the high-affinity, relevant to intoxication, @entity1068 site. The @entity1245 site is specific for certain GABAAR subtypes, mainly synaptic, while the @entity1068 site is found at a modified @entity1245 site on different, extrasynaptic, subtypes. In the transmembrane domain are allosteric modulatory ligand sites for diverse chemotypes of general anesthetics: the volatile and intravenous agents, @entity7353 , @entity4671 , @entity1875 , long-chain @entity4313 , and neurosteroids. The last are endogenous positive allosteric modulators. X-ray crystal structures of prokaryotic and invertebrate pentameric ligand-gated ion channels, and the @entity1 GABAAR protein, allow homology modeling of GABAAR subtypes with the various ligand sites located to suggest the structure and function of these proteins and their pharmacological modulation.
