Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Mar 13

PMID 38474212

Authors

Nhung Thi Hong Van

Woo Kyung Kim

Joo Hyun Nam

Affiliations

Soon will be listed here.

Abstract

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application.

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References

Semenov I, Wang B, Herlihy J, Brenner R . BK channel beta1-subunit regulation of calcium handling and constriction in tracheal smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006; 291(4):L802-10. DOI: 10.1152/ajplung.00104.2006. View

Song P, Du Y, Song W, Chen H, Xuan Z, Zhao L . KCa3.1 as an Effective Target for Inhibition of Growth and Progression of Intrahepatic Cholangiocarcinoma. J Cancer. 2017; 8(9):1568-1578. PMC: 5535712. DOI: 10.7150/jca.18697. View

Zaman T, De Oliveira C, Smoka M, Narla C, Poulter M, Schmid S . BK Channels Mediate Synaptic Plasticity Underlying Habituation in Rats. J Neurosci. 2017; 37(17):4540-4551. PMC: 6596664. DOI: 10.1523/JNEUROSCI.3699-16.2017. View

Goda A, Siddique A, Mohyeldin M, Ayoub N, El Sayed K . The Maxi-K (BK) Channel Antagonist Penitrem A as a Novel Breast Cancer-Targeted Therapeutic. Mar Drugs. 2018; 16(5). PMC: 5983288. DOI: 10.3390/md16050157. View

Thompson J, Ji G, Neugebauer V . Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain. Mol Pain. 2015; 11:51. PMC: 4551697. DOI: 10.1186/s12990-015-0055-9. View

Ma Z, Lou X, Horrigan F . Role of charged residues in the S1-S4 voltage sensor of BK channels. J Gen Physiol. 2006; 127(3):309-28. PMC: 2151507. DOI: 10.1085/jgp.200509421. View

Grover N, Limaye R, Gokhale D, Patil T . Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease. Indian J Pharmacol. 2013; 45(6):547-55. PMC: 3847242. DOI: 10.4103/0253-7613.121266. View

Terentyev D, Rochira J, Terentyeva R, Roder K, Koren G, Li W . Sarcoplasmic reticulum Ca²⁺ release is both necessary and sufficient for SK channel activation in ventricular myocytes. Am J Physiol Heart Circ Physiol. 2014; 306(5):H738-46. PMC: 3949063. DOI: 10.1152/ajpheart.00621.2013. View

Tao X, Hite R, MacKinnon R . Cryo-EM structure of the open high-conductance Ca-activated K channel. Nature. 2016; 541(7635):46-51. PMC: 5500982. DOI: 10.1038/nature20608. View

10.

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

11.

Strobaek D, Brown D, Jenkins D, Chen Y, Coleman N, Ando Y . NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease. Br J Pharmacol. 2012; 168(2):432-44. PMC: 3572569. DOI: 10.1111/j.1476-5381.2012.02143.x. View

12.

Wu Y, Yang Y, Ye S, Jiang Y . Structure of the gating ring from the human large-conductance Ca(2+)-gated K(+) channel. Nature. 2010; 466(7304):393-7. PMC: 2910425. DOI: 10.1038/nature09252. View

13.

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

14.

Michelucci A, Sforna L, Di Battista A, Franciolini F, Catacuzzeno L . Ca -activated K channels regulate cell volume in human glioblastoma cells. J Cell Physiol. 2023; 238(9):2120-2134. DOI: 10.1002/jcp.31072. View

15.

Lin H, Zheng C, Li J, Yang C, Hu L . Ca2+ -activated K+ channel-3.1 blocker TRAM-34 alleviates murine allergic rhinitis. Int Immunopharmacol. 2014; 23(2):642-8. DOI: 10.1016/j.intimp.2014.10.017. View

16.

Dolga A, de Andrade A, Meissner L, Knaus H, Hollerhage M, Christophersen P . Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons. Cell Death Dis. 2014; 5:e999. PMC: 4040692. DOI: 10.1038/cddis.2013.530. View

17.

Agarwal J, Zhu Y, Zhang Q, Mongin A, Hough L . TRAM-34, a putatively selective blocker of intermediate-conductance, calcium-activated potassium channels, inhibits cytochrome P450 activity. PLoS One. 2013; 8(5):e63028. PMC: 3646888. DOI: 10.1371/journal.pone.0063028. View

18.

Sahu G, Turner R . The Molecular Basis for the Calcium-Dependent Slow Afterhyperpolarization in CA1 Hippocampal Pyramidal Neurons. Front Physiol. 2022; 12:759707. PMC: 8730529. DOI: 10.3389/fphys.2021.759707. View

19.

Li Q, Li Y, Wei H, Pan H, Vouga A, Rothberg B . Molecular determinants of Ca sensitivity at the intersubunit interface of the BK channel gating ring. Sci Rep. 2018; 8(1):509. PMC: 5765161. DOI: 10.1038/s41598-017-19029-8. View

20.

Weiger T, Holmqvist M, Levitan I, Clark F, Sprague S, Huang W . A novel nervous system beta subunit that downregulates human large conductance calcium-dependent potassium channels. J Neurosci. 2000; 20(10):3563-70. PMC: 6772688. View