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

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.

Cooperativity between calmodulin-binding sites in Kv7.2 channels

“…A clue to explain this disparity came recently when the influence of the elevated endogenous CaM levels on Kv7.2 function in oocytes was highlighted (Etzioni et al, 2011). Alternatively, the difference in CaM-dependency between Xenopus oocytes and HEK293 cells may arise from distinct post-translational modifications of the channel, such as phosphorylation of the CaM-binding site by protein kinase C (PKC) (Kosenko et al, 2012) or modifications of CaM, such as casein kinase (CK2)-dependent phosphorylation (Bildl et al, 2004). The CaM concentration in oocytes has been estimated to be ,34 mM (Cartaud et al, 1980), 36% higher than in HEK293 cells (Black et al, 2004).…”

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Binding of ghrelin to its receptor GHS-R1a causes the activation of PLC and the following hydrolyzation of PIP 2 . The product of PIP 2 hydrolyzation, diacylglycerol (DAG), activates PKC, resulting in the phosphorylation of KCNQ channels (for example, S541 of KCNQ2) 34 and its closure, which elicits reduced outward potassium current and enhances neuronal excitability of SNc dopamine neurons.…”

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

“…CaM binding is essential for Kv7 channels to exit from the endoplasmic reticulum, and influences heteromeric assembly of Kv7.2/3 channels and subsequent enrichment at the axonal initial segment (Yus-Nájera et al, 2002;Devaux et al, 2004;Chung et al, 2006;Etxeberria et al, 2008;Haitin and Attali, 2008;Alaimo et al, 2009;Cavaretta et al, 2014;Chung, 2014;Liu and Devaux, 2014). CaM regulatory mechanisms that change the gating behavior proceed through an effect on sensitivity to PIP 2 (Kosenko et al, 2012;Kosenko and Hoshi, 2013;Zaydman et al, 2013;Kang et al, 2014). The interlinker between helices A and B is not essential for function, although it plays a critical role in PIP 2 regulation for Kv7.3, but not in Kv7.1 and Kv7.2 channels (Hernandez et al, 2008;Aivar et al, 2012;Sachyani et al, 2014).…”