Functional coupling between heterologously expressed dopamine D(2) receptors and KCNQ channels

Activation of KCNQ potassium channels by stimulation of co-expressed dopamine D₂ receptors was studied electrophysiologically in Xenopus laevis oocytes and in mammalian cells. To address the specificity of the interaction between D₂-like receptors and KCNQ channels, combinations of KCNQ1–5 channels and D₂-like receptors (D_2L, D₃, and D₄) were investigated in Xenopus oocytes. Activation of either receptor with the selective D₂-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 GTPS and prevented by injection of Bordetella pertussis toxin, indicating that channel stimulation was mediated via a G protein of the G_i/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_V1.1, and K_V4.3) 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 D₂ 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.