PIP(2) 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 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.
Zhang
Hailin
H
Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.
Craciun
Liviu C
LC
Mirshahi
Tooraj
T
Rohács
Tibor
T
Lopes
Coeli M B
CM
Jin
Taihao
T
Logothetis
Diomedes E
DE
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006868:Hydrolysis; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D018613:Microscopy, Confocal; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000502:physiology*; D011994:Recombinant Proteins; D015290:Second Messenger Systems; D015398:Signal Transduction; D017783:Superior Cervical Ganglion / Q000166:cytology; D019789:Tetraethylammonium / Q000494:pharmacology; D014162:Transfection; D000077191:Wortmannin; D014982:Xenopus laevis
D000730:Androstadienes; D004791:Enzyme Inhibitors; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C496915:Kcnq2 protein, rat; C496918:Kcnq3 protein, rat; D019269:Phosphatidylinositol 4,5-Diphosphate; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D019789:Tetraethylammonium; D001920:Bradykinin; D000077191:Wortmannin