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

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. 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. 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.

Campostrini G ，Bonzanni M ，Lissoni A ，Bazzini C ，Milanesi R ，Vezzoli E ，Francolini M ，Baruscotti M ，Bucchi A ，Rivolta I ，Fantini M ，Severi S ，Cappato R ，Crotti L ，J Schwartz P ，DiFrancesco D ，Barbuti A ... -  《-》

Long-QT syndrome-associated caveolin-3 mutations differentially regulate the hyperpolarization-activated cyclic nucleotide gated channel 4.

Motloch LJ ，Larbig R ，Darabi T ，Reda S ，Motloch KA ，Wernly B ，Lichtenauer M ，Gebing T ，Schwaiger A ，Zagidullin N ，Wolny M ，Hoppe UC ... -  《Physiology International》

Caveolin-3 and Caveolae regulate ventricular repolarization.

Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk. To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart. Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QTc interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (Ito, Iss) and changes in inward currents including slowed inactivation of ICa,L and increased INa,L. Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD. We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.

Markandeya YS ，Gregorich ZR ，Feng L ，Ramchandran V ，O' Hara T ，Vaidyanathan R ，Mansfield C ，Keefe AM ，Beglinger CJ ，Best JM ，Kalscheur MM ，Lea MR ，Hacker TA ，Gorelik J ，Trayanova NA ，Eckhardt LL ，Makielski JC ，Balijepalli RC ，Kamp TJ ... -  《-》

Caveolin-3 and Caveolin-1 Interaction Decreases Channel Dysfunction Due to Caveolin-3 Mutations.

Benzoni P ，Gazzerro E ，Fiorillo C ，Baratto S ，Bartolucci C ，Severi S ，Milanesi R ，Lippi M ，Langione M ，Murano C ，Meoni C ，Popolizio V ，Cospito A ，Baruscotti M ，Bucchi A ，Barbuti A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro.

Traverso M ，Gazzerro E ，Assereto S ，Sotgia F ，Biancheri R ，Stringara S ，Giberti L ，Pedemonte M ，Wang X ，Scapolan S ，Pasquini E ，Donati MA ，Zara F ，Lisanti MP ，Bruno C ，Minetti C ... -  《-》