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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/C81    most recent 00028.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Liu, B. Articles by Zhang, H. PubMed PubMed Citation Articles by Liu, B. Articles by Zhang, H.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

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 (PIP₂) hydrolysis mediated by stimulation of H₁ receptor and phospholipase C (PLC). Histamine inhibited KCNQ2/Q3 currents in HEK293 cells coexpressing H₁ receptor, and this effect was totally abolished by H₁ receptor antagonist mepyramine but not altered by H₂ receptor antagonist cimetidine. The inhibition of KCNQ currents was significantly attenuated by a PLC inhibitor U-73122 but not affected by depletion of internal Ca²⁺ stores or intracellular Ca²⁺ concentration ([Ca²⁺]_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 PIP₂ was impaired with phosphatidylinsitol-4-kinase inhibitors. Histamine was capable of producing a reversible translocation of the PIP₂ fluorescence probe PLC₁-PH-GFP from membrane to cytosol in HEK293 cells by activation of H₁ 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 PIP₂ by PLC.

superior cervical ganglion; phosphatidylinositol 4,5-bisphosphate; calcium ion