Cerebellar GABAB receptors modulate function of GABAA receptors.
Interactions between GABAA and GABAB receptors were studied using muscimol-stimulated uptake of 36Cl- by membrane vesicles from mouse cerebellum. Baclofen inhibited muscimol-stimulated 36Cl- uptake and this action was more pronounced with longer flux times (30 vs. 3 s) and after predesensitization of GABAA receptors. Baclofen also inhibited 36Cl- flux by cortical membranes but was more effective with cerebellar preparations. The action of baclofen was stereoselective, calcium-dependent, and blocked by the GABAB 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 GABAB receptors can inhibit the function of GABAA receptors and suggest that this action involves either a nondesensitizing subtype of GABAA receptor or the rate or 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 GABAA receptor by protein kinase C.
Hahner
L
L
Veterans Administration Medical Center, Denver, Colorado.
McQuilkin
S
S
Harris
R A
RA
D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001464:Barium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D002713:Chlorine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D009118:Muscimol / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004963:Estrenes; D011760:Pyrrolidinones; D011963:Receptors, GABA-A; D013757:Tetraethylammonium Compounds; C034882:guanosine 5'-O-(1-thiotriphosphate); C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D001464:Barium; D009118:Muscimol; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002713:Chlorine; D019789:Tetraethylammonium; D010738:Type C Phospholipases; D001418:Baclofen; D002118:Calcium; C057491:2-hydroxysaclofen