Evidence for pharmacologically distinct subsets of GABAB receptors.
Activation of GABAB receptors augments neurotransmitter-stimulated cyclic AMP accumulation while inhibiting forskolin-mediated second messenger production. Previous studies have revealed that GABAB receptors are associated with a pertussis toxin sensitive G protein, such as Gi. While such a linkage is consistent with the finding that GABAB receptor activation inhibits forskolin-mediated second messenger accumulation, it fails to explain how GABAB agonists are capable of augmenting receptor-mediated cyclic AMP production. The present experiments were undertaken to explore the possible existence of pharmacologically distinct GABAB receptors in an attempt to explain this apparent discrepancy. For the study, a variety of agents were examined for their ability to inhibit GABAB 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 GABAB 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 GABAB receptor function in other systems, the results indicate a multiplicity of pharmacologically distinct GABAB receptor recognition sites. This discovery paves the way for the development of more selective GABAB receptor agonists and antagonists possessing different therapeutic potentials.
Scherer
R W
RW
Nova Pharmaceutical Corporation, Baltimore, MD 21224-2788.
Ferkany
J W
JW
Enna
S J
SJ
D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001667:Binding, Competitive; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000145:classification* / Q000187:drug effects / Q000378:metabolism
D011437:Propylamines; D011963:Receptors, GABA-A; C052329:phaclofen; D005576:Colforsin; D000242:Cyclic AMP; D001418:Baclofen; D007545:Isoproterenol; C011649:3-aminopropylphosphonic acid