Channelopathy of small- and intermediate-conductance Ca2+-activated K+ channels

Small- and intermediate-conductance Ca2+-activated K+ (K(Ca)2.x/K(Ca)3.1 also called SK/IK) channels are gated exclusively by intracellular Ca2+. The Ca2+ binding protein calmodulin confers sub-micromolar Ca2+ sensitivity to the channel-calmodulin complex. The calmodulin C-lobe is constitutively associated with the proximal C-terminus of the channel. Interactions between calmodulin N-lobe and the channel S4-S5 linker are Ca2+-dependent, which subsequently trigger conformational changes in the channel pore and open the gate. KCNN genes encode four subtypes, including KCNN1 for K(Ca)2.1 (SK1), KCNN2 for K(Ca)2.2 (SK2), KCNN3 for K(Ca)2.3 (SK3), and KCNN4 for K(Ca)3.1 (IK). The three K(Ca)2.x channel subtypes are expressed in the central nervous system and the heart. The K(Ca)3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional K(Ca)2.x/K(Ca)3.1 channels on human health has not been well documented. Human loss-of-function K(Ca)2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca2+ sensitivity of K(Ca)2.3 and K(Ca)3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of K(Ca)2.x/K(Ca)3.1 channels, the pathophysiology of the diseases linked with K(Ca)2.x/K(Ca)3.1 mutations, the structure-function relationship of the mutant K(Ca)2.x/K(Ca)3.1 channels, and potential pharmacological therapeutics for the K(Ca)2.x/K(Ca)3.1 channelopathy.

Automated summary

Small- and intermediate-conductance Ca2+-activated K+ channels, known as SK/IK channels, play important roles in human body. Mutations in the K(Ca)2.x/K(Ca)3.1 channels are associated with various diseases, including neurodevelopmental disorders and hereditary conditions. This review article discusses the physiological significance, pathophysiology, structure-function relationship, and potential pharmacological therapeutics of K(Ca)2.x/K(Ca)3.1 channels.