Phosphatidylinositol 4,5-bisphosphate hydrolysis mediates histamine-induced KCNQ/M current inhibition

Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei Province, China Submitted 22 January 2008 ; accepted in final form 27 April 2008 The M-type potassium channel, of which its molecular basis is constituted by KCNQ2-5 homo- or heteromultimers, plays a key role in regulating neuronal excitability and is modulated by many G protein-coupled receptors. In this study, we demonstrate that histamine inhibits KCNQ2/Q3 currents in human embryonic kidney (HEK)293 cells via phosphatidylinositol 4,5-bisphosphate (PIP 2 ) hydrolysis mediated by stimulation of H 1 receptor and phospholipase C (PLC). Histamine inhibited KCNQ2/Q3 currents in HEK293 cells coexpressing H 1 receptor, and this effect was totally abolished by H 1 receptor antagonist mepyramine but not altered by H 2 receptor antagonist cimetidine. The inhibition of KCNQ currents was significantly attenuated by a PLC inhibitor U-73122 but not affected by depletion of internal Ca 2+ stores or intracellular Ca 2+ concentration ([Ca 2+ ] i ) buffering via pipette dialyzing BAPTA. Moreover, histamine also concentration dependently inhibited M current in rat superior cervical ganglion (SCG) neurons by a similar mechanism. The inhibitory effect of histamine on KCNQ2/Q3 currents was entirely reversible but became irreversible when the resynthesis of PIP 2 was impaired with phosphatidylinsitol-4-kinase inhibitors. Histamine was capable of producing a reversible translocation of the PIP 2 fluorescence probe PLC 1 -PH-GFP from membrane to cytosol in HEK293 cells by activation of H 1 receptor and PLC. We concluded that the inhibition of KCNQ/M currents by histamine in HEK293 cells and SCG neurons is due to the consumption of membrane PIP 2 by PLC. superior cervical ganglion; phosphatidylinositol 4,5-bisphosphate; calcium ion Address for reprint requests and other correspondence: H. Zhang, Dept. of Pharmacology, Hebei Medical Univ., 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China (e-mail: zhanghl{at}hebmu.edu.cn )