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Cardiovasc Res. 2017 Aug 1;113(10):1256-1265. doi: 10.1093/cvr/cvx122.

The expression of the rare caveolin-3 variant T78M alters cardiac ion channels function and membrane excitability.

Author information

1
Department of Biosciences, The PaceLab, Università degli Studi di Milano, Milano, Italy.
2
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano, Italy.
3
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
4
Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), Università degli Studi di Milano, Milano, Italy.
5
Department of Health Science, Università di Milano Bicocca, Monza, Italy.
6
Cellular and Molecular Engineering Laboratory 'S. Cavalcanti', Department of Electrical, Electronic and Information Engineering 'Guglielmo Marconi', University of Bologna, Bologna, Italy.
7
Arrhythmia & Electrophysiology Unit II, Humanitas Gavazzeni Clinics, Bergamo, Italy.
8
Arrhythmia & Electrophysiology Research Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
9
Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milano, Italy.
10
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
11
Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy.

Abstract

Aims:

Caveolinopathies are a family of genetic disorders arising from alterations of the caveolin-3 (cav-3) gene. The T78M cav-3 variant has been associated with both skeletal and cardiac muscle pathologies but its functional contribution, especially to cardiac diseases, is still controversial. Here, we evaluated the effect of the T78M cav-3 variant on cardiac ion channel function and membrane excitability.

Methods and results:

We transfected either the wild type (WT) or T78M cav-3 in caveolin-1 knock-out mouse embryonic fibroblasts and found by immunofluorescence and electron microscopy that both are expressed at the plasma membrane and form caveolae. Two ion channels known to interact and co-immunoprecipitate with the cav-3, hKv1.5 and hHCN4, interact also with T78M cav-3 and reside in lipid rafts. Electrophysiological analysis showed that the T78M cav-3 causes hKv1.5 channels to activate and inactivate at more hyperpolarized potentials and the hHCN4 channels to activate at more depolarized potentials, in a dominant way. In spontaneously beating neonatal cardiomyocytes, the expression of the T78M cav-3 significantly increased action potential peak-to-peak variability without altering neither the mean rate nor the maximum diastolic potential. We also found that in a small cohort of patients with supraventricular arrhythmias, the T78M cav-3 variant is more frequent than in the general population. Finally, in silico analysis of both sinoatrial and atrial cell models confirmed that the T78M-dependent changes are compatible with a pro-arrhythmic effect.

Conclusion:

This study demonstrates that the T78M cav-3 induces complex modifications in ion channel function that ultimately alter membrane excitability. The presence of the T78M cav-3 can thus generate a susceptible substrate that, in concert with other structural alterations and/or genetic mutations, may become arrhythmogenic.

KEYWORDS:

Arrhythmia; Caveolin; Electrophysiology; Genetic diseases; Ion channels

PMID:
28898996
PMCID:
PMC5852518
DOI:
10.1093/cvr/cvx122
[Indexed for MEDLINE]
Free PMC Article

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