Channelopathy-Causing Mutations in the S₄₅A/S₄₅B and HA/HB Helices of K_Ca2.3 and K_Ca3.1 Channels Alter Their Apparent Ca²⁺ Sensitivity

Authors

Razan Orfali, Chapman UniversityFollow
Young-Woo Nam, Chapman University
Hai Minh Nguyen, University of California, Davis
Mohammad Asikur Rahman, Chapman University
Grace Yang, Chapman University
Meng Cui, Northeastern UniversityFollow
Heike Wulff, University of California, Davis
Miao Zhang, Chapman UniversityFollow

Document Type

Article

Publication Date

1-8-2022

Abstract

Small- and intermediate-conductance Ca²⁺-activated potassium (K_Ca2.x and K_Ca3.1, also called SK and IK) channels are activated exclusively by a Ca²⁺-calmodulin gating mechanism. Wild-type K_Ca2.3 channels have a Ca²⁺ EC₅₀ value of ∼0.3 μM, while the apparent Ca²⁺ sensitivity of wild-type K_Ca3.1 channels is ∼0.27 μM. Heterozygous genetic mutations of K_Ca2.3 channels have been associated with Zimmermann-Laband syndrome and idiopathic noncirrhotic portal hypertension, while K_Ca3.1 channel mutations were reported in hereditary xerocytosis patients. K_Ca2.3_S436C and K_Ca2.3_V450L channels with mutations in the S₄₅A/S₄₅B helices exhibited hypersensitivity to Ca²⁺. The corresponding mutations in K_Ca3.1 channels also elevated the apparent Ca²⁺ sensitivity. K_Ca3.1_S314P, K_Ca3.1_A322V and K_Ca3.1_R352H channels with mutations in the HA/HB helices are hypersensitive to Ca²⁺, whereas K_Ca2.3 channels with the equivalent mutations are not. The different effects of the equivalent mutations in the HA/HB helices on the apparent Ca²⁺ sensitivity of K_Ca2.3 and K_Ca3.1 channels may imply distinct modulation of the two channel subtypes by the HA/HB helices. AP14145 reduced the apparent Ca²⁺ sensitivity of the hypersensitive mutant K_Ca2.3 channels, suggesting the potential therapeutic usefulness of negative gating modulators.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Cell Calcium. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Cell Calcium, volume 102, in 2022. https://doi.org/10.1016/j.ceca.2022.102538

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Recommended Citation

Orfali R, Nam Y-W, Nguyen HM, et al. Channelopathy-causing mutations in the S₄₅A/S₄₅B and HA/HB helices of K_Ca2.3 and K_Ca3.1 channels alter their apparent Ca²⁺ sensitivity. Cell Calcium. 2022;102:102538. https://doi.org/10.1016/j.ceca.2022.102538

Copyright

Elsevier

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.