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

The gamma-aminobutyric acid type A (GABA(A)) receptor is the predominant Cl--channel protein mediating inhibition in the retina and elsewhere in the mammalian brain. We have observed a time-dependent increase of GABA-induced whole-cell currents when dopamine was applied externally to rat retinal amacrine cells. After 20 min, the Peak current was increased to 208% +/- 10% of its initial value. A comparable effect was observed with the dopamine D-1 receptor agonist (+)-1-phenyl-2,3,4,5-tetrahydro(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) but not with the D-2 agonist bromocryptine. The action of dopamine involved phosphorylation of GABA(A) receptors by protein kinase A, as evident from intracellular application of protein kinase A, cAMP, and forskolin. Both guanosine 5'-[gamma-thio]triphosphate and cholera toxin augmented the GABA response, indicating a role for the guanosine 5'-triphosphate-binding protein G(s) in the transduction cascade. Phosphorylation of GABA(A) receptors shifted the half-maximally effective GABA concentration from 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 vasoactive intestinal peptide were found to couple to the same intracellular phosphorylation pathway. Since some of these cotransmitters colocalize with GABA in amacrine cells, they may fine-tune GABAergic inhibition in the retina.