Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation |
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Authors: | Kosenko Anastasia Kang Seungwoo Smith Ida M Greene Derek L Langeberg Lorene K Scott John D Hoshi Naoto |
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Affiliation: | Department of Pharmacology, University of California, Irvine, CA 92697, USA. |
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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. |
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Keywords: | calmodulin protein complex protein kinase C signal transduction voltage‐gated potassium channel |
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