Activation of KCNQ potassium channels by stimulation of co-expressed dopamine D(2) receptors was studied electrophysiologically in Xenopus laevis oocytes and in mammalian cells. To address the specificity of the interaction between D(2)-like receptors and KCNQ channels, combinations of KCNQ1-5 channels and D(2)-like receptors (D(2L), D(3), and D(4)) were investigated in Xenopus oocytes. Activation of either receptor with the selective D(2)-like receptor agonist quinpirole (100 nM) stimulated all the KCNQ currents, independently of the subunit combination, indicating a common pathway of receptor-channel interaction. The KCNQ4 current was investigated in further detail and was increased by 19.9+/-1.6% ( n=20) by D(2L) receptor stimulation. The effect could be mimicked by injection of GTPgammaS and prevented by injection of Bordetella pertussis toxin, indicating that channel stimulation was mediated via a G protein of the G(alphai/o) subtype. Cells of the human neuroblastoma line SH-SY5Y were co-transfected transiently with KCNQ4 and D(2L) receptors. Stimulation of D(2L) receptors increased the KCNQ4 current ( n=6) as determined in whole-cell patch-clamp recordings. The specificity of the dopaminergic activation of the KCNQ channels was confirmed by co-expression of other neuronal K(+) channels (BK, K(V)1.1, and K(V)4.3) with the D(2L) receptor in Xenopus oocytes. None of these K(+) channels responded to stimulation of the D(2L) receptor. In the mammalian brain, dopamine D(2) receptors and KCNQ channels co-localise postsynaptically in several brain regions, so modulation of neuronal excitability by dopamine release could in part be mediated via an effect on KCNQ channels.