Pharmacology of GABA-mediated inhibition of spinal cord neurons in vivo and in primary dissociated cell culture.
In this paper it is shown that the postsynaptic GABA-receptor chloride ion channel complex is composed of several functional subunits. There are probably at least two stereospecific locations on the receptor for GABA-binding and both must be occupied to obtain an increase in chloride conductance. The interaction between these sites is uncertain but there could be either positive cooperativity between the sites or only a requirement that both sites are occupied without occupation of either site affecting the affinity for GABA of the other site. There is a chloride conductance channel coupled to the GABA receptor which opens for an average of 20 msec and has an average conductance of 18 pS. The GABA-coupled chloride channel may or may not have the same composition as the glycine coupled chloride channel. In addition to the GABA-recognition site and the chloride ion channel, GABA-receptors must have additional binding sites or modulator sites where drugs can bind to modify GABA activation of the GABA receptor. The convulsant PICRO binds to a site which is independent of the GABA site and PICRO reduces GABA responses. Barbiturates and benzodiazepines augment GABA-responses without reducing GABA-binding and thus they must bind to a modulator site independent of the GABA recognition site. Whether or not this is the same site as the PICRO binding site is uncertain. Thus, the GABA-receptor-chloride ion channel complex is composed of at least: 1) two GABA-binding sites; 2) a chloride ion channel; 3) a convulsant binding site (PICRO-binding site) and 4) an anticonvulsant binding site. This organization serves several obvious purposes. First, since two GABA-molecules are required to activate GABA-coupled chloride ion channels, the dose-response relationship for GABA is sigmoidal and steep. Thus minor shifts in GABA affinity will produce large alterations in GABA-responses and the GABA receptor can be easily modulated. Second, since the receptors has binding sites for convulsant and anticonvulsant compounds which decrease and increase GABA-responses, GABAergic inhibition can easily be modulated.
D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D004553:Electric Conductivity; D018756:GABA Antagonists; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology; D011963:Receptors, GABA-A; D013116:Spinal Cord / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D002712:Chlorides; D018756:GABA Antagonists; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D011188:Potassium