Pharmacology of novel GABA receptors found on rod horizontal cells of the white perch retina

Abstract

A novel type of GABA receptor is present on rod-driven (H4) horizontal cells of the white perch retina (Qian and Dowling, 1993a). These receptors have been tentatively termed GABA(C) receptors. In this study, the pharmacological properties of these receptors were further investigated by applying several conformationally restricted GABA(A) receptor agonists, GABA(A) antagonists, and a GABA(B) agonist to the H4 horizontal cells. GABA analogs locked in a partially folded conformation had a variety of effects. Isonipecotic acid had no effect on these receptors, whereas isoguvacine activated them but with low potency (EC50 = 137 μM). THIP (4,5,6,7- tetrahydroisoxazolo[5,4-c]pyridin-3-ol) acted as a competitive antagonist on these receptors with an inhibition constant of 82.5 μM. P4S (piperidine-4- sulfonic acid) activated the receptors at high concentrations (>1 mM), but at lower concentrations it was a competitive antagonist with an inhibition constant of 80.9 μM. 14AA (imidazole-4-acetic acid), a GABA analog with an extended conformation, potently inhibited the GABA responses on H4 horizontal cells with an inhibition constant of 1.67 μM. Muscimol, which can assume both partially folded and extended conformations, acted as a mixed agonist- antagonist. The GABA responses on H4 horizontal cells were resistant to several competitive GABA(A) receptor antagonists including bicuculline, hydrastine, and SR-95531, but they were very sensitive to picrotoxin (IC50 = 237 nM). The inhibition by picrotoxin was both competitive and non- competitive in nature. On the other hand, TBPS (tert-butyl- bicyclophosphorothionate), another GABA(A) receptor channel blocker, had minimal effects on these receptors. The specific GABA(B) agonist 3-APA (3- aminopropyl phosphonic acid) acted as a competitive antagonist on H4 horizontal cells with an inhibition constant of 43 μM. The GABA responses on the horizontal cells were also resistant to strychnine, a glycine receptor antagonist. The results provide further evidence that the GABA receptors on H4 horizontal cells in perch are pharmacologically distinct from known GABA receptors, supporting the designation of GABA(C) receptors for them.