PIP2 Activates KCNQ Channels, and Its Hydrolysis Underlies Receptor-Mediated Inhibition of M Currents

KCNQ channels belong to a family of potassium ion channels with crucial roles in physiology and disease. Heteromers of KCNQ2/3 subunits constitute the neuronal M channels. Inhibition of M currents, by pathways that stimulate phospholipase C activity, controls excitability throughout the nervous syst...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2003-03, Vol.37 (6), p.963-975
Main Authors: Zhang, Hailin, Craciun, Liviu C, Mirshahi, Tooraj, Rohács, Tibor, Lopes, Coeli M.B, Jin, Taihao, Logothetis, Diomedes E
Format: Article
Language:English
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Grants
Kinases
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Summary:KCNQ channels belong to a family of potassium ion channels with crucial roles in physiology and disease. Heteromers of KCNQ2/3 subunits constitute the neuronal M channels. Inhibition of M currents, by pathways that stimulate phospholipase C activity, controls excitability throughout the nervous system. Here we show that a common feature of all KCNQ channels is their activation by the signaling membrane phospholipid phosphatidylinositol-bis-phosphate (PIP2). We show that wortmannin, at concentrations that prevent recovery from receptor-mediated inhibition of M currents, blocks PIP2replenishment to the cell surface. Moreover, we identify a C-terminal histidine residue, immediately proximal to the plasma membrane, mutation of which renders M channels less sensitive to PIP2and more sensitive to receptor-mediated inhibition. Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP2. Our data strongly suggest that PIP2acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents.
ISSN:0896-6273
1097-4199
DOI:10.1016/S0896-6273(03)00125-9