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PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.

Hailin Zhang, Liviu C Craciun, Tooraj Mirshahi, Tibor Rohacs, Coeli M B Lopes, Taihao Jin, Diomedes E Logothetis

Neuron, 2003 Mar 27 , 37, 963-75

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 (PIP(2)). We show that wortmannin, at concentrations that prevent recovery from receptor-mediated inhibition of M currents, blocks PIP(2) replenishment 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 PIP(2) and more sensitive to receptor-mediated inhibition. Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP(2). Our data strongly suggest that PIP(2) acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents.

http://www.ncbi.nlm.nih.gov/pubmed/12670425