Biochemical and electrophysiological characteristics of mammalian GABA receptors.

The concept that GABA is a neurotransmitter in the mammalian CNS is supported by both electrophysiological and biochemical data. Whereas the electrophysiological studies are essential for demonstrating a specific functional response to GABA, the biochemical approach is useful for characterizing the molecular properties of this site. As a result of these studies the concept of the GABA receptor has progressed from a simple model of a single recognition site associated with a chloride channel to a more complex structure having a variety of interacting components. Thus, both electrophysiological and biochemical data support the existence of at least two pharmacologically distinct types of GABA receptors, based on the sensitivity to bicuculline. Also, anatomically, there appear to be two different types of receptors, those located postsynaptically on the soma or dendrites of a neighboring cell and those found presynaptically on GABAergic and other neurotransmitter terminals. From biochemical studies it appears that the GABA receptor may be composed of at least three distinct interacting components. One of these, the recognition site, may exist in two conformations, with one preferring agonists and the other having a higher affinity for antagonists. Ion channels may be considered a second component, with some of these regulating the passage of chloride ion, whereas others may be associated with calcium transport. The third major element of GABA receptors appears to be a benzodiazepine recognition site, although only a certain population of GABA receptors may be endowed with this property. In addition to these, the GABA receptor complex appears to contain substances that modulate the recognition site by influencing the availability of higher affinity binding proteins. It would appear therefore that changes affecting any one of these constituents can influence the characteristics of the others. While increasing the complexity of the system, this arrangement makes for a more sensitive and adaptable receptor mechanism. Thus the GABA receptor can be envisioned as a supramolecular complex of interacting sites, all of which contribute to the functional expression of receptor activation. Because of this complexity, GABA receptors can theoretically be modified in a variety of ways by drug treatment or disease. Accordingly, it may be possible to develop selective agonists and antagonists that may act at one of the basic components, as well as agents that may alter the receptor modulators. Conversely, a disorder of any of these entities may result in an alteration of GABA receptor function, which in turn could contribute to the symptoms of a variety of neuropsychiatric disorders.(ABSTRACT TRUNCATED AT 400 WORDS)