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

Abstract

AimsCaveolinopathies 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 resultsWe 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.ConclusionThis 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.

Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients

“…In particular, it has been characterized as a variant of unknown or benign significance after it has been found in healthy individuals with frequencies comparable to cases with long QT syndrome [ 55 , 56 ]. Even though this variant has been found also in the patient’s asymptomatic father, we ascribe this to a possible concerted action with another yet unidentified variant that predisposes to the specific phenotypic characteristics, as it has been previously suggested for the role of p.Thr78Met CAV3 in cardiac diseases [ 57 ].…”

Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle

“…Caveolin 3 (Cav3) is a caveolin family member protein expressed in cell types that act as a scaffolding protein for the organization and concentration of certain caveolin-interacting molecules. Mutations in this gene is attributed to lead to Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia, or rippling muscle disease (RMD) (39). It has been reported that Cav3 expression in mice is primarily in heart and skeletal muscle (40).…”

Functional Microdomains in Heart’s Pacemaker: A Step Beyond Classical Electrophysiology and Remodeling

“…Cav-3, the integral membrane protein that is essential in formation of caveolae (Figures 1 , 2 ), is also linked with SND ( Lang et al, 2016 ; Campostrini et al, 2017 ). As discussed in the previous sections, Cav-3 is involved in the regulation of multiple ion channels and transporters, including those involved in pacemaking.…”

“…Cav-3 F97C and S141R mutations have been linked to the long QT type 9 inherited arrhythmia syndrome (LQT9) causing AP duration prolongation which had been attributed to an increase in late Na + current ( Vatta et al, 2006 ). In spontaneously beating neonatal cardiomyocytes, the expression of the T78M mutation in CAV3 gene significantly increased AP peak-to-peak variability without altering neither the mean rate nor the maximum diastolic potential ( Campostrini et al, 2017 ) and was associated with a positive shift of activation of HCN4 channels, in a dominant way. The authors also identified a small cohort of patients with supraventricular arrhythmias including sinus tachycardia, bradycardia, and atrial fibrillation where the T78M Cav-3 variant is more frequent than in the general population.…”