Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation.
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.
Department of Pharmacology, University of California, Irvine, CA 92697, USA.
Anastasia
A
Kosenko
Seungwoo
S
Kang
Ida M
IM
Smith
Derek L
DL
Greene
Lorene K
LK
Langeberg
John D
JD
Scott
Naoto
N
Hoshi
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology*
D051658:KCNQ2 Potassium Channel; C496915:Kcnq2 protein, rat; D019269:Phosphatidylinositol 4,5-Diphosphate; D011976:Receptors, Muscarinic; D011493:Protein Kinase C