Evidence for pharmacologically distinct subsets of GABA_B receptors

Activation of GABA_B receptors augments neurotransmitter-stimulated cyclic AMP accumulation while inhibiting forskolin-mediated second messenger production. Previous studies have revealed that GABA_B receptors are associated with a pertussis toxin sensitive G protein, such as G_i. While such a linkage is consistent with the finding that GABA_B receptor activation inhibits forskolin-mediated second messenger accumulation, it fails to explain how GABA_B agonists are capable of augmenting receptor-mediated cyclic AMP production. The present experiments were undertaken to explore the possible existence of pharmacologically distinct GABA_B receptors in an attempt to explain this apparent discrepancy. For the study, a variety of agents were examined for their ability to inhibit GABA_B binding to brain membranes and to modify isoproterenol- or forskolin-stimulated second messenger production in rat brain slices. Of the compounds studied, only 3-aminopropylphosphonic acid and 4-aminobutylphosphonic acid were found to inhibit GABA_B binding. However, 4-aminobutylphosphonic acid failed to influence either isoproterenol- or forskolin-stimulated cyclic AMP production. On the other hand, while 3-aminopropylphosphonic acid also failed to affect isoproterenol-stimulated second messenger accumulation, it inhibited the forskolin-mediated response. Given this finding, and the fact that some of the agents tested are known to influence GABA_B receptor function in other systems, the results indicate a multiplicity of pharmacologically distinct GABA_B receptor recognition sites. This discovery paves the way for the development of more selective GABA_B receptor agonists and antagonists possessing different therapeutic potentials.