Long QT syndrome caveolin‐3 mutations differentially modulate Kv4 and Cav1.2 channels to contribute to action potential prolongation

Key points

Mutations in the caveolae scaffolding protein, caveolin‐3 (Cav3), have been linked to the long QT type 9 inherited arrhythmia syndrome (LQT9), and the cause of underlying action potential duration prolongation is incompletely understood. Here, we show that LQT9 Cav3 mutations, F97C and S141R, cause mutation‐specific gain of function effects on Ca_v1.2‐encoded L‐type Ca²⁺ channels responsible for I_Ca,L and cause loss of function effects on heterologously expressed K_v4.2 and K_v4.3 channels responsible for I_to. A computational model of the human ventricular myocyte action potential suggests that the major ionic current change causing APD prolongation in the presence of Cav3‐F97C is the slowly inactivating I_Ca,L, but for Cav3‐S141R, both increased I_Ca,L and increased late Na⁺ current contribute equally to APD prolongation. Overall, the LQT9 Cav3‐F97C and ‐S141R mutations differentially impact multiple ionic currents highlighting the complexity of Cav3 regulation of cardiac excitability and suggesting mutation‐specific therapeutic approaches.

Abstract

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_v1.2+Ca_vβ_2cN4 channels as well as K_v4.2 and K_v4.3 channels in HEK 293 cells. Expression of Cav3‐S141R increased I_Ca,L density without changes in gating properties, but expression of Cav3‐F97C reduced Ca²⁺‐dependent inactivation of I_Ca,L without changing current density. The Cav3‐F97C mutation reduced current density and altered the kinetics of I_Kv4.2 and I_Kv4.3 as well as slowed recovery from inactivation. Cav3‐S141R decreased current density, 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, while blunted Ca²⁺‐dependent inactivation of I_Ca,L by Cav3‐F97C is predicted to be primarily responsible for APD prolongation, but increased I_Ca,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 mutation‐specific therapeutic approaches in the future.

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