PRESYNAPTIC INHIBITION BY GABA IS MEDIATED VIA 2 DISTINCT GABA RECEPTORS WITH NOVEL PHARMACOLOGY

Mechanisms of presynaptic inhibition were examined in giant presynaptic terminals of retinal bipolar neurons, which receive GABAergic feedback synapses from amacrine cells. Two distinct inhibitory actions of GABA are present in the terminals: a GABA(A)-like Cl conductance and a GABA(B)-like inhibition of voltage-dependent Ca current. Both of the receptors underlying these actions have unusual pharmacology that fits neither GABA(A) nor GABA(B) classifications. The GABA-activated Cl conductance was not blocked by the classical GABA(A) antagonist bicuculline, while the inhibition of Ca current was neither mimicked by the GABA(B) agonist baclofen nor blocked by the GABA(B) antagonist 2-hydroxysaclofen. The ''GABA(C)'' agonist cis-4-aminocrotonic acid (CACA) both activated the Cl conductance and inhibited Ca current, but the inhibition of Ca current was observed at much lower concentrations of CACA (<1 mu M) than was the activation of the Cl conductance (K-1/2 = 50 mu M). Thus, by the criterion of being insensitive to both bicuculline and baclofen, both GABA receptors qualify as potential GABA(C) receptors. However, it is argued on functional grounds that the two GABA receptors coupled to Cl channels and to Ca channels are best regarded as members of the GABA(A) and GABA(B) families, respectively.