Perspectives in Pharmacology g-Aminobutyric AcidB Receptors: First of the Functional Metabotropic Heterodimers

Activation of the metabotropic g-aminobutyric acidB (GABAB) receptor increases K conductance and decreases Ca channel activity in neuronal membranes. Studies with a number of new GABAB receptor agonists and antagonists reveal that in addition to their muscle relaxant effects, agonists display analgesic activity and reduce the craving for cocaine. With regard to GABAB receptor antagonists, preclinical data suggest they improve cognitive performance and possess antidepressant and antiepileptic potential. With a high-affinity GABAB antagonist, the structural properties of the receptor were characterized through expression cloning. Moreover, it has been found that expression of a fully functional GABAB receptor requires coupling between two separate and distinct gene products: GABAB R1 and GABAB R2. Besides being the first example of a functional heterodiameric metabotropic receptor, the components and molecular configuration of the GABAB receptor suggest novel mechanisms for producing pharmacologically distinct subtypes of G protein-coupled receptors. The g-aminobutyric acidB (GABAB) receptor (GBR) was identified nearly 20 years ago as a result of studies aimed at determining whether chloride-dependent GABA receptors are present on peripheral nerve terminals as they are on primary afferent terminals in spinal cord. Although the data indicated that GABA receptors are present on sympathetic nerve endings and that their activation reduced the evoked release of neurotransmitters, their pharmacological properties were quite different from those of the classic GABA receptor. For example, GABA-mediated inhibition of neurotransmitter release from rat sympathetic nerve terminals is not inhibited by bicuculline and is not mimicked by isoguvacine, an antagonist and agonist, respectively, for the chloride-dependent GABA receptor. On the other hand, this receptor was stereoselectively activated by b-chlorophenyl GABA (baclofen), an antispastic agent that displays no affinity for the classic GABA receptor. Together, these and other findings suggested the existence of a GABA receptor subtype distinct from the chloride-dependent receptor system. This new receptor, termed GABAB, like the classic GABAA receptor, is widely distributed throughout the mammalian brain and spinal cord, suggesting it plays an important role in maintaining central nervous system function (Hill and Bowery, 1981).