PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents

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

Research output: Contribution to journalArticlepeer-review

387 Scopus citations

Abstract

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 PIP2 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 PIP2 and 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 PIP2 acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents.

Original languageEnglish (US)
Pages (from-to)963-975
Number of pages13
JournalNeuron
Volume37
Issue number6
DOIs
StatePublished - Mar 27 2003

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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