Long Qt Syndrome Caveolin-3 Mutations Differentially Modulate K(V)4 And Ca(V)1.2 Channels To Contribute To Action Potential Prolongation

Mutations in the CAV3 gene encoding caveolin-3 (Cav3), a scaffolding protein integral to caveolae in cardiomyocytes, have been associated with the congenital long-QT syndrome (LQT9). Initial studies demonstrated that LQT9-associated Cav3 mutations, F97C and S141R, increase late sodium current as a potential mechanism to prolong action potential duration (APD) and cause LQT9. Whether these Cav3 LQT9 mutations impact other caveolae related ion channels remains unknown. We used the whole-cell, patch clamp technique to characterize the effect of Cav3-F97C and Cav3-S141R mutations on heterologously expressed Ca(v)1.2+Ca-v beta(2cN4) channels, as well as K(v)4.2 and K(v)4.3 channels, in HEK 293 cells. Expression of Cav3-S141R increased I-Ca,I-L density without changes in gating properties, whereas expression of Cav3-F97C reduced Ca2+-dependent inactivation of I-Ca,I-L without changing current density. The Cav3-F97C mutation reduced current density and altered the kinetics of I-Kv4.2 and I-Kv4.3 and also slowed recovery from inactivation. Cav3-S141R decreased current density and also slowed activation kinetics and recovery from inactivation of I-Kv4.2 but had no effect on I-Kv4.3. Using the O'Hara-Rudy computational model of the human ventricular myocyte action potential, the Cav3 mutation-induced changes in I-to are predicted to have negligible effect on APD, whereas blunted Ca2+-dependent inactivation of I-Ca,I-L by Cav3-F97C is predicted to be primarily responsible for APD prolongation, although increased I-Ca,I-L and late I-Na by Cav3-S141R contribute equally to APD prolongation. Thus, LQT9 Cav3-associated mutations, F97C and S141R, produce mutation-specific changes in multiple ionic currents leading to different primary causes of APD prolongation, which suggests the use of mutation-specific therapeutic approaches in the future.