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

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.

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

Fig. 1. K_Ca2.2 channel structure and LOF mutations.

a Human K_Ca2.2 channel homology model generated using human K_Ca3.1 channel (PDB: 6cnn) as a template. Pore-forming channel α-subunits are shown in salmon and its accessory CaM is shown in gray. Mutations are shown as spheres with carbon atoms in green, oxygen atoms in red, and nitrogen atoms in dark blue. Mutations in only one of the four α-subunits are shown for clarity. In the inset, the relative position of CaM N-lobe, the S4-S5 linker (S₄₅A and S₄₅B helices), and HA helix is shown. b Mutations in selectivity filter and transmembrane S6 domain of channel pore. Mutations in only one of two opposite α-subunits are shown for clarity. c Schematic representation of one K_Ca2.2 channel subunit. Pathogenic LOF mutations are shown as green circles. a, b were generated using Pymol (Schrödinger LLC). c was generated using Biorender.com

Fig. 2. K_Ca2.3 channel structure and GOF mutations.

a Human K_Ca2.3 channel homology model generated using human K_Ca3.1 channel (PDB: 6cnn) as a template. Pore-forming channel α-subunits are shown in pale blue and its accessory CaM is shown in gray. Mutations are shown as spheres with carbon atoms in magenta, oxygen atoms in red and nitrogen atoms in dark blue. Mutations in only one of the four α-subunits are shown for clarity. In the inset, the relative position of CaM N-lobe, the S4-S5 linker (S₄₅A and S₄₅B helices), and HA helix are shown. b Mutations in the transmembrane S6 domain of channel pore. Mutations in only one of two opposite α-subunits are shown for clarity. c Schematic representation of one K_Ca2.3 channel subunit. Pathogenic GOF mutations are shown as red circles. a, b were generated using Pymol (Schrödinger LLC). c was generated using Biorender.com

Fig. 3. K_Ca3.1 channel structure and GOF mutations.

a Human K_Ca3.1 channel cryo-EM structure (PDB: 6cnn). Pore-forming channel α-subunits are shown in pale green, and its accessory CaM is shown in gray. Mutations are shown as spheres with carbon atoms in magenta, oxygen atoms in red and nitrogen atoms in dark blue. Mutations in only one of the four α-subunits are shown for clarity. In the inset, the relative position of CaM C-lobe and HA/HB helices is shown. b The V282 residue defines the narrowest site of the cytoplasmic gate. c Schematic representation of one K_Ca3.1 channel subunit. Pathogenic GOF mutations are shown as red circles. a and b were generated using Pymol (Schrödinger LLC). c was generated using Biorender.com