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

Acta Pharmacol Sin. 2023 Feb;44(2):259-267. doi: 10.1038/s41401-022-00935-1. Epub 2022 Jun 17.

Abstract

Small- and intermediate-conductance Ca2+-activated K+ (KCa2.x/KCa3.1 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 KCa2.1 (SK1), KCNN2 for KCa2.2 (SK2), KCNN3 for KCa2.3 (SK3), and KCNN4 for KCa3.1 (IK). The three KCa2.x channel subtypes are expressed in the central nervous system and the heart. The KCa3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional KCa2.x/KCa3.1 channels on human health has not been well documented. Human loss-of-function KCa2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of KCa2.x/KCa3.1 channels, the pathophysiology of the diseases linked with KCa2.x/KCa3.1 mutations, the structure-function relationship of the mutant KCa2.x/KCa3.1 channels, and potential pharmacological therapeutics for the KCa2.x/KCa3.1 channelopathy.

Keywords: KCa2.2 channels; KCa2.3 channels; KCa3.1 channels; Zimmermann-Laband syndrome; channelopathy; hereditary xerocytosis.

Publication types

  • Review

MeSH terms

  • Calmodulin / genetics
  • Calmodulin / metabolism
  • Channelopathies*
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / genetics
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism
  • Mutation
  • Small-Conductance Calcium-Activated Potassium Channels* / genetics
  • Small-Conductance Calcium-Activated Potassium Channels* / metabolism

Substances

  • Small-Conductance Calcium-Activated Potassium Channels
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Calmodulin