Activation of Phosphatidylinositol-Linked Novel D1 Dopamine Receptors Inhibits High-Voltage-Activated Ca2+ Currents in Primary Cultured Striatal Neurons

Abstract

Recent evidences indicate the existence of a putative novel phosphatidylinositol (PI)-linked D(1) dopamine receptor that mediates excellent anti-Parkinsonian but less severe dyskinesia action. To further understand the basic physiological function of this receptor in brain, the effects of a PI-linked D(1) dopamine receptor-selective agonist 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) on high-voltage activated (HVA) Ca(2+) currents in primary cultured striatal neurons were investigated by whole cell patch-clamp technique. The results indicated that stimulation by SKF83959 induced an inhibition of HVA Ca(2+) currents in a dose-dependent manner in substance-P (SP)-immunoreactive striatal neurons. Application of D(1) receptor, but not D(2), alpha(1) adrenergic, 5-HT receptor, or cholinoceptor antagonist prevented SKF83959-induced reduction, indicating that a D(1) receptor-mediated event assumed via PI-linked D(1) receptor. SKF83959-induced inhibitory modulation was mediated by activation of phospholipase C (PLC), mobilization of intracellular Ca(2+) stores and activation of calcineurin. Furthermore, the inhibitory effects were attenuated significantly by the L-type calcium channel antagonist nifedipine, suggesting that L-type calcium channels involved in the regulation induced by SKF83959. These findings may help to further understand the functional role of the PI-linked dopamine receptor in brain.