Channelopathy of Small- and Intermediate-conductance Ca-activated K Channels

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2022 Jun 17

PMID 35715699

Authors

Young-Woo Nam

Myles Downey

Mohammad Asikur Rahman

Meng Cui

Miao Zhang

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Fluorescent Probes to Image the K3.1 Channel in Tumor Cells.

Thale I, Nass E, Vinnenberg L, Todesca L, Budde T, Maisuls I Pharmaceutics. 2025; 17(2).

PMID: 40006521 PMC: 11859423. DOI: 10.3390/pharmaceutics17020154.

AP-1 activates KCNN4-mediated Ca2 signaling to induce the Th1/Th17 differentiation of CD4 cells in chronic non-bacterial prostatitis.

Teng J, Jia Z, Gao F, Guan Y, Yao L, Ma C Cell Biol Toxicol. 2024; 41(1):18.

PMID: 39729199 PMC: 11680619. DOI: 10.1007/s10565-024-09967-1.

A sexually dimorphic signature of activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the prefrontal cortex.

Ma K, Zhang D, McDaniel K, Webb M, Newton S, Lee F Front Cell Neurosci. 2024; 18():1496930.

PMID: 39569070 PMC: 11576208. DOI: 10.3389/fncel.2024.1496930.

The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity.

Kistamas K, Lamberto F, Vaiciuleviciute R, Leal F, Muenthaisong S, Marte L Int J Mol Sci. 2024; 25(17).

PMID: 39273136 PMC: 11394806. DOI: 10.3390/ijms25179186.

ACYP2 functions as an innovative nano-therapeutic target to impede the progression of hepatocellular carcinoma by inhibiting the activity of TERT and the KCNN4/ERK pathway.

Wu Y, Bao H, Wu J, Chen B, Xu J, Jin K J Nanobiotechnology. 2024; 22(1):557.

PMID: 39267048 PMC: 11391695. DOI: 10.1186/s12951-024-02827-4.

References

DellOrco J, Wasserman A, Chopra R, Ingram M, Hu Y, Singh V . Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability. J Neurosci. 2015; 35(32):11292-307. PMC: 4532759. DOI: 10.1523/JNEUROSCI.1357-15.2015. View

Yu C, Chia-Ti T, Chen P, Wu C, Chiu F, Chiang F . KCNN2 polymorphisms and cardiac tachyarrhythmias. Medicine (Baltimore). 2016; 95(29):e4312. PMC: 5265796. DOI: 10.1097/MD.0000000000004312. View

Andolfo I, Russo R, Manna F, Shmukler B, Gambale A, Vitiello G . Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol. 2015; 90(10):921-6. DOI: 10.1002/ajh.24117. View

Tomita H, Shakkottai V, Gutman G, Sun G, Bunney W, Cahalan M . Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. Mol Psychiatry. 2003; 8(5):524-35, 460. DOI: 10.1038/sj.mp.4001271. View

Tuteja D, Rafizadeh S, Timofeyev V, Wang S, Zhang Z, Li N . Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels. Circ Res. 2010; 107(7):851-9. PMC: 3732376. DOI: 10.1161/CIRCRESAHA.109.215269. View

Balint B, Guerreiro R, Carmona S, Dehghani N, Latorre A, Cordivari C . KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia. Eur J Neurol. 2020; 27(8):1471-1477. DOI: 10.1111/ene.14228. View

Shakkottai V, Chou C, Oddo S, Sailer C, Knaus H, Gutman G . Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Invest. 2004; 113(4):582-90. PMC: 338266. DOI: 10.1172/JCI20216. View

Simo-Vicens R, Kirchhoff J, Dolce B, Abildgaard L, Speerschneider T, Sorensen U . A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K 2) channels. Br J Pharmacol. 2017; 174(23):4396-4408. PMC: 5715977. DOI: 10.1111/bph.14043. View

Ishii T, Silvia C, HIRSCHBERG B, Bond C, Adelman J, Maylie J . A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci U S A. 1997; 94(21):11651-6. PMC: 23567. DOI: 10.1073/pnas.94.21.11651. View

10.

Freise C, Heldwein S, Erben U, Hoyer J, Kohler R, Johrens K . K⁺-channel inhibition reduces portal perfusion pressure in fibrotic rats and fibrosis associated characteristics of hepatic stellate cells. Liver Int. 2014; 35(4):1244-52. DOI: 10.1111/liv.12681. View

11.

Kortum F, Caputo V, Bauer C, Stella L, Ciolfi A, Alawi M . Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet. 2015; 47(6):661-7. DOI: 10.1038/ng.3282. View

12.

Nam Y, Cui M, Orfali R, Viegas A, Nguyen M, Mohammed E . Hydrophobic interactions between the HA helix and S4-S5 linker modulate apparent Ca sensitivity of SK2 channels. Acta Physiol (Oxf). 2020; 231(1):e13552. PMC: 7736289. DOI: 10.1111/apha.13552. View

13.

Gao Q, Yang C, Meng L, Wang Z, Chen D, Peng Y . Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras. J Periodontal Res. 2020; 56(3):471-481. DOI: 10.1111/jre.12836. View

14.

Walter J, Alvina K, Womack M, Chevez C, Khodakhah K . Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006; 9(3):389-97. DOI: 10.1038/nn1648. View

15.

Rapetti-Mauss R, Soriani O, Vinti H, Badens C, Guizouarn H . Senicapoc: a potent candidate for the treatment of a subset of hereditary xerocytosis caused by mutations in the Gardos channel. Haematologica. 2016; 101(11):e431-e435. PMC: 5394861. DOI: 10.3324/haematol.2016.149104. View

16.

Zhang X, Thai P, Lieu D, Chiamvimonvat N . Cardiac small-conductance calcium-activated potassium channels in health and disease. Pflugers Arch. 2021; 473(3):477-489. PMC: 7940285. DOI: 10.1007/s00424-021-02535-0. View

17.

Brown B, Shim H, Christophersen P, Wulff H . Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels. Annu Rev Pharmacol Toxicol. 2019; 60:219-240. PMC: 9615427. DOI: 10.1146/annurev-pharmtox-010919-023420. View

18.

Schwarz M, Ryba L, Krepelova A, Moslerova V, Zelinova M, Turnovec M . Zimmermann-Laband syndrome in monozygotic twins with a mild neurobehavioral phenotype lacking gingival overgrowth-A case report of a novel KCNN3 gene variant. Am J Med Genet A. 2021; 188(4):1083-1087. DOI: 10.1002/ajmg.a.62616. View

19.

Bulaklak K, Gersbach C . The once and future gene therapy. Nat Commun. 2020; 11(1):5820. PMC: 7670458. DOI: 10.1038/s41467-020-19505-2. View

20.

Womack M, Khodakhah K . Somatic and dendritic small-conductance calcium-activated potassium channels regulate the output of cerebellar Purkinje neurons. J Neurosci. 2003; 23(7):2600-7. PMC: 6742089. View