Long QT syndrome-associated calmodulin variants disrupt the activity of the slow delayed rectifier potassium current

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McCormick, Liam, Wadmore, Kirsty, Milburn, Amy, Gupta, Nitika ORCID: 0000-0003-3885-2500, Morris, Rachael, Held, Marie ORCID: 0000-0003-0118-5898, Prakash, Ohm, Carr, Joseph, Barrett-Jolley, Richard ORCID: 0000-0003-0449-9972, Dart, Caroline ORCID: 0000-0002-3509-8349 et al (show 1 more authors) (2023) Long QT syndrome-associated calmodulin variants disrupt the activity of the slow delayed rectifier potassium current. JOURNAL OF PHYSIOLOGY-LONDON, 601 (17). pp. 3739-3764.

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Official URL: http://dx.doi.org/10.1113/jp284994

Abstract

Calmodulin (CaM) is a highly conserved mediator of calcium (Ca2+ )-dependent signalling and modulates various cardiac ion channels. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS). LQTS patients display prolonged ventricular recovery times (QT interval), increasing their risk of incurring life-threatening arrhythmic events. Loss-of-function mutations to Kv7.1 (which drives the slow delayed rectifier potassium current, IKs, a key ventricular repolarising current) are the largest contributor to congenital LQTS (>50% of cases). CaM modulates Kv7.1 to produce a Ca2+ -sensitive IKs, but little is known about the consequences of LQTS-associated CaM mutations on Kv7.1 function. Here, we present novel data characterising the biophysical and modulatory properties of three LQTS-associated CaM variants (D95V, N97I and D131H). We showed that mutations induced structural alterations in CaM and reduced affinity for Kv7.1, when compared with wild-type (WT). Using HEK293T cells expressing Kv7.1 channel subunits (KCNQ1/KCNE1) and patch-clamp electrophysiology, we demonstrated that LQTS-associated CaM variants reduced current density at systolic Ca2+ concentrations (1 μm), revealing a direct QT-prolonging modulatory effect. Our data highlight for the first time that LQTS-associated perturbations to CaM's structure impede complex formation with Kv7.1 and subsequently result in reduced IKs. This provides a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype. KEY POINTS: Calmodulin (CaM) is a ubiquitous, highly conserved calcium (Ca2+ ) sensor playing a key role in cardiac muscle contraction. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS), a life-threatening cardiac arrhythmia syndrome. LQTS-associated CaM variants (D95V, N97I and D131H) induced structural alterations, altered binding to Kv7.1 and reduced IKs. Our data provide a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype.

Item Type:	Article
Uncontrolled Keywords:	calcium, calmodulin, cardiac arrhythmia, IKs, Kv7.1, LQTS
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate
Depositing User:	Symplectic Admin
Date Deposited:	17 Jul 2023 13:41
Last Modified:	04 Oct 2023 13:29
DOI:	10.1113/JP284994
Open Access URL:	https://physoc.onlinelibrary.wiley.com/doi/full/10...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3171733