Functional coupling between heterologously expressed dopamine D2 receptors and KCNQ channels

Abstract

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.

Regulation of KCNQ4 Potassium Channel Prepulse Dependence and Current Amplitude by SGK1 in <i>Xenopus</i> oocytes

“…The reasons for this discrepancy remained elusive but may include unknown interacting proteins like scaffolding proteins, KCNEs, or regulation by ions, kinases, PIP2 and/or further signaling mechanisms. Similar to other KCNQ channels, KCNQ4 channels are downregulated by activation of M1-receptors and upregulated by activation of dopamine D2 receptors [12,13]. Furthermore, cell volume, the protein kinases PKA and PKC, G proteins and intracellular Ca 2+ have been reported to regulate KCNQ4 [14].…”

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Neuronal M-current is a subthreshold voltage-gated K þ current encoded by Kv7/KCNQ channels that modulate firing frequency of mesencephalic dopamine neurons 14 and are functionally coupled to dopamine D2 receptors, providing essential modulatory inputs to their striatal and limbic targets 15,16 . Both Kv7/KCNQ channels and GHS-R are expressed in the SNc, hippocampus, dorsal root ganglion (DRG), hypothalamus and cortex 11,15,[17][18][19][20][21][22][23] .…”

Antipsychotic-Like Effect of Retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic Acid Ester], a KCNQ Potassium Channel Opener, via Modulation of Mesolimbic Dopaminergic Neurotransmission

“…Retigabine was shown to inhibit dopamine (DA) cell firing activity in midbrain slices, block increased DA efflux induced by DA reuptake blockade in the striatum, and inhibit locomotor hyperactivity induced by various psychostimulants (Hansen et al, 2006(Hansen et al, , 2007. There is also evidence that somatodendritic dopamine D 2 receptors are functionally coupled to KCNQ channels in DA neurons and that the modulation of DAergic activity by D 2 autoreceptors would involve the activation of KCNQ2 and/or KCNQ4 subunits (Ljungstrom et al, 2003). Abnormal regulation of DA neurons in the ventral tegmental area (VTA) is believed to be involved in the etiology of psychotic symptoms.…”