Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation

• Published in: The EMBO journal 2012-07, Vol.31 (14), p.3147-3156
• Main Authors: Kosenko, Anastasia, Kang, Seungwoo, Smith, Ida M, Greene, Derek L, Langeberg, Lorene K, Scott, John D, Hoshi, Naoto
• Format: Article
• Language: English
• Subjects: Animals; calmodulin; CHO Cells; Cricetinae; Cricetulus; EMBO27; EMBO37; HEK293 Cells; Humans; Ion Channel Gating - physiology; KCNQ2 Potassium Channel - genetics; KCNQ2 Potassium Channel - metabolism; Neurotransmitters; Phosphatidylinositol 4,5-Diphosphate - genetics; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phosphorylation - physiology; Potassium; protein complex; protein kinase C; Protein Kinase C - genetics; Protein Kinase C - metabolism; Rats; Receptors, Muscarinic - genetics; Receptors, Muscarinic - metabolism; Second Messenger Systems - physiology; Signal transduction; voltage-gated potassium channel
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2012.156

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. Neurotransmitters govern the action potential threshold of M‐channels, encoded by the KCNQ gene family. Muscarine promotes PKC‐mediated phosphorylation of KCNQ2 to regulate calmodulin binding, which determines PIP2 affinity and channel activity.