Long QT syndrome caveolin-3 mutations differentially modulate K v 4 and Ca v 1.2 channels to contribute to action potential prolongation

Leonid Tyan, Jason D. Foell, Kevin P. Vincent, Marites T. Woon, Walatta T. Mesquitta, Di Lang, Jabe M. Best, Michael J. Ackerman, Andrew D. McCulloch, Alexey V. Glukhov, Ravi C. Balijepalli, Timothy J. Kamp

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5 Scopus citations

Abstract

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. In the present study, we show that LQT9 Cav3 mutations, F97C and S141R, cause mutation-specific gain of function effects on Ca v 1.2-encoded L-type Ca 2+ channels responsible for I Ca,L and also cause loss of function effects on heterologously expressed K v 4.2 and K v 4.3 channels responsible for I to . A computational model of the human ventricular myocyte action potential suggests that the major ionic current change causing action potential duration 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 action potential duration prolongation. Overall, the LQT9 Cav3-F97C and Cav3-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 v 1.2+Ca v β 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,L density without changes in gating properties, whereas expression of Cav3-F97C reduced Ca 2+ -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 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 Ca 2+ -dependent inactivation of I Ca,L by Cav3-F97C is predicted to be primarily responsible for APD prolongation, although 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 the use of mutation-specific therapeutic approaches in the future.

Original languageEnglish (US)
Pages (from-to)1531-1551
Number of pages21
JournalJournal of Physiology
Volume597
Issue number6
DOIs
StatePublished - Mar 15 2019

Keywords

  • arrhythmia
  • cardiac electrophysiology
  • cardiac potassium current
  • caveola
  • computer modeling
  • voltage-dependent calcium channel

ASJC Scopus subject areas

  • Physiology

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    Tyan, L., Foell, J. D., Vincent, K. P., Woon, M. T., Mesquitta, W. T., Lang, D., Best, J. M., Ackerman, M. J., McCulloch, A. D., Glukhov, A. V., Balijepalli, R. C., & Kamp, T. J. (2019). Long QT syndrome caveolin-3 mutations differentially modulate K v 4 and Ca v 1.2 channels to contribute to action potential prolongation Journal of Physiology, 597(6), 1531-1551. https://doi.org/10.1113/JP276014