Coordinated Signal Integration at the M-type Potassium Channel Upon Muscarinic Stimulation

EMBO J. 2012 May 29;31(14):3147-56. doi: 10.1038/emboj.2012.156.

Abstract

Several neurotransmitters, including acetylcholine, regulate neuronal tone by suppressing a non-inactivating low-threshold voltage-gated potassium current generated by the M-channel. Agonist dependent control of the M-channel is mediated by calmodulin, activation of anchored protein kinase C (PKC), and depletion of the phospholipid messenger phosphatidylinositol 4,5-bisphosphate (PIP2). In this report, we show how this trio of second messenger responsive events acts synergistically and in a stepwise manner to suppress activity of the M-current. PKC phosphorylation of the KCNQ2 channel subunit induces dissociation of calmodulin from the M-channel complex. The calmodulin-deficient channel has a reduced affinity towards PIP2. This pathway enhances the effect of concomitant reduction of PIP2, which leads to disruption of the M-channel function. These findings clarify how a common lipid cofactor, such as PIP2, can selectively regulate ion channels.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / physiology*
  • KCNQ2 Potassium Channel / genetics
  • KCNQ2 Potassium Channel / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / genetics
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphorylation / physiology
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Rats
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism*
  • Second Messenger Systems / physiology*

Substances

  • KCNQ2 Potassium Channel
  • Kcnq2 protein, rat
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Muscarinic
  • Protein Kinase C