Dopamine activates inward rectifier K+ channel in acutely dissociated rat substantia nigra neurones

The effect of dopamine (DA) was investigated on acutely dissociated rat sub stantia nigra pars compacta (SNc) neurones by using patch clamp recording. The SNc neurones could be classified into two groups. About 75% of large ne urones (>30 mu m in diameter) were tyrosine hydroxylase (TH) positive while almost all small neurones (<20 mu m) were TH negative. In the large neuron es, DA hyperpolarized the membrane, resulting in a reduction of the frequen cy of spontaneous action potentials in current-clamp mode and induced an in ward rectifier K+ current in voltage-clamp mode. Quinpirole, a D-2 receptor agonist, mimicked the DA action. S(-)-sulpiride, a D-2 receptor antagonist , inhibited the DA-induced current (I-DA) more effectively than SKF83566, a D-1 receptor antagonist. Intracellular application of either guanosine 5'- O-(2-thiodiphosphate) (GDP-beta S) or pertussis toxin (IAP) suppressed I-DA . Guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma S) sustained the DA respon se. Modulators for cAMP such as forskolin and isobutylmethylxathine, H-89, a protein kinase A inhibitor, and chelerythrine, a protein kinase C inhibit or, had no effect on I-DA. The frequency of DA-induced single channel curre nts in the inside-out patch configuration, for which the unitary conductanc e was 56.6pS, was greatly reduced by the replacement of GTP with GDP perfus ed at the cytosolic side. These results suggest that DA acts on a D-2-like receptor and activates directly an IAP-sensitive G protein coupled with inw ard rectifier K+ channels, resulting in a decrease in the spontaneous firin g activities of rat SNc dopaminergic neurones. (C) 2000 Elsevier Science Lt d. All rights reserved.