Channelopathy of small- and intermediate-conductance Ca-activated K channels.

Small- and intermediate-conductance Ca-activated K (K2.x/K3.1 also called SK/IK) channels are gated exclusively by intracellular Ca. The Ca binding protein calmodulin confers sub-micromolar Ca 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 Ca-dependent, which subsequently trigger conformational changes in the channel pore and open the gate. KCNN genes encode four subtypes, including KCNN1 for K2.1 (SK1), KCNN2 for K2.2 (SK2), KCNN3 for K2.3 (SK3), and KCNN4 for K3.1 (IK). The three K2.x channel subtypes are expressed in the central nervous system and the heart. The K3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional K2.x/K3.1 channels on human health has not been well documented. Human loss-of-function K2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca sensitivity of K2.3 and K3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of K2.x/K3.1 channels, the pathophysiology of the diseases linked with K2.x/K3.1 mutations, the structure-function relationship of the mutant K2.x/K3.1 channels, and potential pharmacological therapeutics for the K2.x/K3.1 channelopathy.