Abstract
The ubiquitous calcium transducer calmodulin (CaM) plays a pivotal role in many cellular processes, regulating a myriad of structurally different target proteins. Indeed, it is unquestionable that CaM is the most relevant transductor of calcium signals in eukaryotic cells. During the last two decades, different studies have demonstrated that CaM mediates the modulation of several ion channels. Among others, it has been indicated that Kv7.2 channels, one of the members of the voltage gated potassium channel family that plays a critical role in brain excitability, requires CaM binding to regulate the different mechanisms that govern its functions. The purpose of this review is to provide an overview of the most recent advances in structure–function studies on the role of CaM regulation of Kv7.2 and the other members of the Kv7 family.
Highlights
The ubiquitous calcium transducer calmodulin (CaM) plays a pivotal role in many cellular processes, regulating a myriad of structurally different target proteins
The molecular mechanism underlying this Ca2+ -dependent regulation of an ion channel remained obscure until the ‘90s when it was suggested that CaM could mediate the regulation of Ca2+ -dependent Na+ - and K+ -channels in Paramecium [11,12]
We found that mutations in helix A (hA) and helix B (hB) underlying benign familiar neonatal convulsions (BFNC), an autosomal dominant form of neonatal epilepsy, weakened CaM binding, leading to reduced currents as a consequence of an endoplasmic reticulum (ER) retention of Kv7.2 subunits
Summary
Calmodulin (CaM) is the member of EF-hand proteins superfamily which are important Ca2+. The Naoto Hoshi’s group demonstrated that the phosphorylation of CaM, mediated by casein kinase 2, enhanced the binding with Kv7.2, induced resistance to PIP2 depletion, leading to an augmentation on Kv7.2 current amplitude [62] In accordance with these findings, Gomis-Perez and colleagues found that expression and availability of apoCaM alter the PIP2 regulation of Kv7.2 and Kv7.3 channels [60]. Another paper, performing a live-cell FRET study combined with an electrophysiological-based analysis, provided evidence of a functional connection between CaM binding, PIP2 dependency and the distal coiled-coil tetramerization domain in Kv7.2 channels [35]. New observations underlined the reciprocal connection between the hAB domain and the coiled-coil module through CaM-mediated regulation of the stability of the distal tetramerization domain of Kv7.2 channels [63]
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