Functional coupling of presynaptic GABAB receptors with voltage-gated Ca2+ channel: regulation by protein kinases A and C in cultured spinal cord neurons.
Depolarization-induced 86Rb efflux, an index of K+ efflux, was developed by using mammalian cultured spinal cord neurons to study the effect of gamma aminobutyric acid (GABAB) receptor activation on Ca2(+)-activated K(+)-channels. The Ca2(+)-activated 86Rb efflux was obtained by using two methods. The first method utilized depolarizing concentrations of KCl (100 mM) to study the voltage-gated Ca2+ channel activation, whereas in the second method, calcium ionophore A23187 was used to get the voltage-independent Ca2(+)-activated 86Rb efflux. The GABAB receptor agonist baclofen inhibited the efflux induced by depolarization but not by A23187, whereas tricyclic antidepressant desipramine inhibited the efflux induced by both depolarization and A23187. These results suggest that the GABAB receptor activation inhibits 86Rb efflux by inhibiting the voltage-gated Ca2+ channels. Moreover, forskolin and the analogs of cAMP antagonized the action of baclofen, suggesting that the GABAB receptors are negatively coupled to adenylate cyclase. Furthermore, protein kinase C activators antagonized this action of baclofen, while the antagonists of protein kinase C reversed their action on baclofen. In addition, the inactive forskolin, 1,9-dideoxyl forskolin, and the inactive phorbol analog, phorbol 12,13-didecanoate, did not influence the action of baclofen. Thus, it is suggested that the GABAB receptor activation inhibited the voltage-gated Ca2+ influx and that this action is under modulatory control by kinases A and C.
Kamatchi
G L
GL
Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
Ticku
M K
MK
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D010703:Phorbol Esters / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology
D015220:Calcium Channels; D010703:Phorbol Esters; D011963:Receptors, GABA-A; D000001:Calcimycin; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D011188:Potassium