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

Neuron. 2003 Mar 27;37(6):963-75. doi: 10.1016/s0896-6273(03)00125-9.

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 (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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Bradykinin / pharmacology
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Electric Conductivity
  • Enzyme Inhibitors / pharmacology
  • Female
  • Hydrolysis
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Microscopy, Confocal
  • Mutation
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Channels / genetics
  • Potassium Channels / physiology*
  • Potassium Channels, Voltage-Gated
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / physiology*
  • Recombinant Proteins
  • Second Messenger Systems
  • Signal Transduction
  • Superior Cervical Ganglion / cytology
  • Tetraethylammonium / pharmacology
  • Transfection
  • Wortmannin
  • Xenopus laevis

Substances

  • Androstadienes
  • Enzyme Inhibitors
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Kcnq2 protein, rat
  • Kcnq3 protein, rat
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • Recombinant Proteins
  • Tetraethylammonium
  • Bradykinin
  • Wortmannin