Regulatory Mechanisms of Ca²⁺-activated Ion Channels and Their Impacts on Physiological/Pathophysiological Functions

Ca²⁺ influx through Ca²⁺ channels localized in the plasma membrane and organelle membrane is involved in robust physiological reactions as a second messenger. In excitable cells such as neurons and myocytes, voltage dependent Ca²⁺ channels propagate electrical signals by forming action potentials and at the same time initiate Ca²⁺ signaling. On the other hand, in non-excitable cells such as immune cells and chondrocytes, voltage independent Ca²⁺ channels such as TRP channels and Ca²⁺ release-activated Ca²⁺ channels are responsible for Ca²⁺ signaling. Ca²⁺ influx through these Ca²⁺ channels is critically regulated by Ca²⁺-activated K⁺ (K_Ca) channels: membrane hyperpolarization due to the activation of K_Ca channels suppresses Ca²⁺ influx in excitable cells but promotes it in non-excitable cells. K_Ca channels are classified into three subtypes: BK, IK, and SK channels. K_Ca channels are often localized near Ca²⁺ channels in the cell membrane or organelle membrane and form Ca²⁺ microdomains because of rapid removal of free Ca²⁺ from cytosol. This enables K_Ca channels to be efficiently activated at physiological membrane potential, convert local Ca²⁺ signals into electrical signals, and modulate Ca²⁺ channel activity as feedback mechanisms. As for BK channel, its activity, e.g. voltage dependence, Ca²⁺ sensitivity and drug sensitivity, and intracellular localization are largely modified by (i) accessory subunits such as β and γ subunits and (ii) alternative splicing. Thus, BK channel can acquire tissue specificity. Furthermore, BK channel activity is also modulated by kinases/phosphatases, reactive oxygen species, and endogenous ligands. In addition to K_Ca channels, Ca²⁺-activated Cl^- channels such as TMEM16A are also involved in the conversion of Ca²⁺ into electrical signals. Ryanodine receptors amplify an increase in intracellular Ca²⁺ concentration by means of Ca²⁺-induced Ca²⁺ release and cause membrane hyperpolarization via activation of K_Ca channels. Various kinds of Ca²⁺-activated ion channels construct complicated network and finely control membrane potential, intracellular Ca²⁺ signaling and thus physiological responses.

This topic focuses on novel mechanisms that control K_Ca channel functions and their outputs as physiological or pathophysiological responses at molecular, organellar, cellular, tissue, and whole body-levels. Especially, it appears crucial to collect more information on protein-protein interaction as well as functional coupling via Ca²⁺ that characterize K_Ca channel functions in each tissue. The goal of this Research Topic is to build the latest platform of knowledge on K_Ca channels and other Ca²⁺-activated ion channels and contribute to the further progress of this research area. 

Scope of this Research Topic may include (but is not limited to) (i) regulatory mechanisms that modulate gene/protein levels, intracellular localization and functions of K_Ca channels by alternative splicing, accessory subunits, protein-protein interactions with cellular components such as Ca²⁺ channels and scaffold proteins, (ii) physiological impact of K_Ca channels based on above mechanisms, and (iii) roles of K_Ca channels in intracellular organelles such as mitochondria, lysosome and nucleus. Original research and review article submissions are welcome in this Research Topic. Articles regarding other Ca²⁺-activated ion channels are also acceptable.