The Crossroad of Ion Channels and Calmodulin in Disease

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Abstract

Calmodulin (CaM) is the principal Ca ²⁺ sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes that encode identical CaM proteins lead to major cardiac dysfunction, revealing the importance in the regulation of excitability. In turn, some mutations at the CaM binding site of ion channels cause similar diseases. Here we provide a summary of the two sides of the partnership between CaM and ion channels, describing the diversity of consequences of mutations at the complementary CaM binding domains.

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hERG potassium channels and cardiac arrhythmia.

Michael C. Sanguinetti, Martin Tristani-Firouzi (2006)

hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.

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Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report.

P Brugada, J Brugada (1992)

The objectives of this study were to present data on eight patients with recurrent episodes of aborted sudden death unexplainable by currently known diseases whose common clinical and electrocardiographic (ECG) features define them as having a distinct syndrome different from idiopathic ventricular fibrillation. Among patients with ventricular arrhythmias who have no structural heart disease, several subgroups have been defined. The present patients constitute an additional subgroup with these findings. The study group consisted of eight patients, six male and two female, with recurrent episodes of aborted sudden death. Clinical and laboratory data and results of electrocardiography, electrophysiology, echocardiography, angiography, histologic study and exercise testing were available in most cases. The ECG during sinus rhythm showed right bundle branch block, normal QT interval and persistent ST segment elevation in precordial leads V1 to V2-V3 not explainable by electrolyte disturbances, ischemia or structural heart disease. No histologic abnormalities were found in the four patients in whom ventricular biopsies were performed. The arrhythmia leading to (aborted) sudden death was a rapid polymorphic ventricular tachycardia initiating after a short coupled ventricular extrasystole. A similar arrhythmia was initiated by two to three ventricular extrastimuli in four of the seven patients studied by programmed electrical stimulation. Four patients had a prolonged HV interval during sinus rhythm. One patient receiving amiodarone died suddenly during implantation of a demand ventricular pacemaker. The arrhythmia of two patients was controlled with a beta-adrenergic blocking agent. Four patients received an implantable defibrillator that was subsequently used by one of them, and all four are alive. The remaining patient received a demand ventricular pacemaker and his arrhythmia is controlled with amiodarone and diphenylhydantoin. Common clinical and ECG features define a distinct syndrome in this group of patients. Its causes remain unknown.

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Calcium and Excitation-Contraction Coupling in the Heart

David A. Eisner, Jessica L Caldwell, Kornel Kistamas … (2017)

Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 18 January 2019

Publication date Collection: January 2019

Volume: 20

Issue: 2

Electronic Location Identifier: 400

Affiliations

[1 ]Biofisika Institute (CSIC, UPV/EHU), University of the Basque Country, 48940 Leioa, Spain; janire.urrutia@ 123456gmail.com (J.U.); alejandra.aguado@ 123456ehu.eus (A.A.); arantza.muguruza.montero@ 123456gmail.com (A.M.-M.); enviadero@ 123456gmail.com (E.N.); covadonga.m@ 123456gmail.com (C.M.)

[2 ]Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco (UPV/EHU), 01006 Vitoria-Gasteiz, Spain; oscar.casis@ 123456ehu.eus

Author notes

[* ]Correspondence: alvaro.villarroel@ 123456csic.es ; Tel.: +34-9460-13225

[†]

These authors contributed equally to this work.

Author information

Janire Urrutia https://orcid.org/0000-0002-8546-292X

Alejandra Aguado https://orcid.org/0000-0003-4709-7711

Eider Núñez https://orcid.org/0000-0001-8075-9815

Article

Publisher ID: ijms-20-00400

DOI: 10.3390/ijms20020400

PMC ID: 6359610

PubMed ID: 30669290

SO-VID: 9aa9eb67-3288-49ab-9bc4-02a34d52e4a4

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

The Crossroad of Ion Channels and Calmodulin in Disease

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Neuronal Signaling

Most cited references 106

hERG potassium channels and cardiac arrhythmia.

Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report.

Calcium and Excitation-Contraction Coupling in the Heart

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