G proteins modulate D2 receptor-coupled K(ATP) channels in rat dopaminergic terminals

The presynaptic dopamine (DA) D2 receptor-mediated regulation of ATP-sensit ive potassium (K-ATP(+)) channels was examined in slices of the rat caudate -putamen. When slices were incubated with the specific D2 receptor antagoni st (-)-sulpiride (SLP), a concentration-dependent increase of extracellular DA release was observed. SLP-induced enhancement was completely antagonize d by coincubation with the Kc,,, channel opener diazoxide (DIA). Treatment of slices with the D2 receptor agonist quinpirole (QUI) almost completely i nhibited DA outflow induced by the K-ATP(+) channel blocker butanedione-mon oxime (BDM). Coincubation of SLP and guanosine triphosphate (GTP) or its no n-hydrolizable analogue guanylyl-5 ' -imidodiphosphate [Gpp(NH)p], signific antly reduced the SLP-induced effect on DA levels. Furthermore, we observed that BDM-induced DA outflow was markedly inhibited by G protein activators suggesting an additional receptor-independent regulation of K-ATP(+) chann el gating. Our results suggest that PTX-sensitive G proteins are involved i n the signal transduction between D2 receptors and K-ATP(+) channels. Furth ermore, K-ATP(+) channels can be modulated in a receptor-independent mechan ism by G protein activators.