CEREBELLAR GABA-B RECEPTORS MODULATE FUNCTION OF GABA-A RECEPTORS

Interactions between GABA(A) and GABA(B) receptors were studied using muscimol-stimulated uptake of Cl-36- by membrane vesicles from mouse cerebellum. Baclofen inhibited muscimol-stimulated Cl-36- uptake and this action was more pronounced with longer flux times (30 vs. 3 s) and after predesensitization of GABA(A) receptors. Baclofen also inhibited Cl-36- flux by cortical membranes but was more effective with cerebellar preparations. The action of baclofen was stereoselective, calcium-dependent, and blocked by the GABA(B) receptor antagonist 2-OH-saclofen. It was mimicked by GTP-gamma-S but not by GDP-beta-S, which suggests that baclofen may be acting via a G protein. The action of baclofen was inhibited by U73122, an inhibitor of phospholipase C. However, the potassium channel blockers tetraethylammonium or Ba2+ did not affect the action of baclofen. The results show that activation of GABA(B) receptors can inhibit the function of GABA(A) receptors and suggest that this action involves either a nondesensitizing subtype of GABA(A) receptor or the rate of recycling of desensitized to nondesensitized receptors. We speculate that this action of baclofen results from activation of phospholipase C and phosphorylation of a subtype of GABA(A) receptor by protein kinase C.