FACILITATION OF GABAERGIC SIGNALING IN THE RETINA BY RECEPTORS STIMULATING ADENYLATE-CYCLASE

The gamma-aminobutyric acid type A (GABA(A)) receptor is the predomina nt Cl--channel protein mediating inhibition in the retina and elsewher e in the mammalian brain. We have observed a time-dependent increase o f GABA-induced whole-cell currents when dopamine was applied externall y to rat retinal amacrine cells. After 20 min, the Peak current was in creased to 208% +/- 10% of its initial value. A comparable effect was observed with the dopamine D-1 receptor agonist enyl-2,3,4,5-tetrahydr o(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) but not with th e D-2 agonist bromocryptine. The action of dopamine involved phosphory lation of GABA(A) receptors by protein kinase A, as evident from intra cellular application of protein kinase A, cAMP, and forskolin. Both gu anosine 5'-[gamma-thio]triphosphate and cholera toxin augmented the GA BA response, indicating a role for the guanosine 5'-triphosphate-bindi ng protein G(s) in the transduction cascade. Phosphorylation of GABA(A ) receptors shifted the half-maximally effective GABA concentration fr om 71 mu M to 47 mu M without affecting the maximal response amplitude . The elevated binding affinity for GABA was caused by an increase of the open probability of the channels from 0.09 to 0.33 (2 mu M GABA); conductance and mean open time did not change. Several other receptor agonists such as adenosine, histamine, somatostatin, enkephalin, and v asoactive intestinal peptide were found to couple to the same intracel lular phosphorylation pathway. Since some of these cotransmitters colo calize with GABA in amacrine cells, they may fine-tune GABAergic inhib ition in the retina.