Channelopathy of Small- and Intermediate-Conductance Ca²⁺-activated K⁺ Channels

Authors

Young-Woo Nam, Chapman University
Myles Downey, Chapman University
Mohammad Asikur Rahman, Chapman University
Meng Cui, Northeastern UniversityFollow
Miao Zhang, Chapman UniversityFollow

Document Type

Article

Publication Date

6-17-2022

Abstract

Small- and intermediate-conductance Ca²⁺-activated K⁺ (K_Ca2.x/K_Ca3.1 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_Ca2.1 (SK1), KCNN2 for K_Ca2.2 (SK2), KCNN3 for K_Ca2.3 (SK3), and KCNN4 for K_Ca3.1 (IK). The three K_Ca2.x channel subtypes are expressed in the central nervous system and the heart. The K_Ca3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional K_Ca2.x/K_Ca3.1 channels on human health has not been well documented. Human loss-of-function K_Ca2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca²⁺ sensitivity of K_Ca2.3 and K_Ca3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of K_Ca2.x/K_Ca3.1 channels, the pathophysiology of the diseases linked with K_Ca2.x/K_Ca3.1 mutations, the structure–function relationship of the mutant K_Ca2.x/K_Ca3.1 channels, and potential pharmacological therapeutics for the K_Ca2.x/K_Ca3.1 channelopathy.

Comments

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Acta Pharmacologica Sinica in 2022 following peer review. The final publication may differ and is available at Springer via https://doi.org/10.1038/s41401-022-00935-1.

A free-to-read copy of the final published article is available here.

Recommended Citation

Nam, YW., Downey, M., Rahman, M.A. et al. Channelopathy of small- and intermediate-conductance Ca²⁺-activated K⁺ channels. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00935-1

Copyright

Springer