PHARMACOLOGY OF NOVEL GABA RECEPTORS FOUND ON ROD HORIZONTAL CELLS OFTHE WHITE PERCH RETINA

A novel type of GABA receptor is present on rod-driven (H4) horizontal cells of the white perch retina (Qian and Dowling, 1993a). These rece ptors have been tentatively termed GABA(C) receptors. In this study, t he pharmacological properties of these receptors were further investig ated by applying several conformationally restricted GABA(A) receptor agonists, GABA(A) antagonists, and a GABA(B) agonist to the H4 horizon tal cells. GABA analogs locked in a partially folded conformation had a variety of effects. Isonipecotic acid had no effect on these recepto rs, whereas isoguvacine activated (t)hem but with low potency (EC(50) = 137 mu M) THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) acte d as a competitive antagonist on these receptors with an inhibition co nstant of 82.5 mu M. P4S (piperidine-4-sulfonic acid) activated the re ceptors at high concentrations(> 1 mM), but at lower concentrations it was a competitive antagonist with an inhibition constant of 80.9 mu M . I4AA (imidazole-44-acetic acid), a GABA analog with an extended conf ormation, potently inhibited the GABA responses on H4 horizontal cells with an inhibition constant of 1.67 mu M Muscimol, which can assume b oth partially folded and extended conformations, acted as a mixed agon ist-antagonist, The GABA responses on H4 horizontal cells were resista nt to several competitive GABA(A) receptor antagonists including bicuc ulline, hydrastine, and SR-95531, but they were very sensitive to picr otoxin (IC50 = 237 nM). The inhibition by picrotoxin was both competit ive and noncompetitive in nature. On the other hand, TBPS (tert-butyl- bicyclophosphorothionate), another GABA(A) receptor channel blocker, h ad minimal effects on these receptors. The specific GABA(B) agonist 3- APA (3-aminopropyl phosphonic acid) acted as a competitive antagonist on 1-14 horizontal cells with an inhibition constant of 43 mu M. The G ABA responses on the horizontal cells were also resistant to strychnin e, a glycine receptor antagonist. The results provide further evidence that the GABA receptors on H4 horizontal cells in perch are pharmacol ogically distinct from known GABA receptors, supporting the designatio n of GABA(C) receptors for them.