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

Autor: Tyan L; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Foell JD; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Vincent KP; Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Woon MT; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Mesquitta WT; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Lang D; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Best JM; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Ackerman MJ; Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN, USA., McCulloch AD; Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, USA.; Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Glukhov AV; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Balijepalli RC; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA., Kamp TJ; Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, 1111, Highland Ave, Madison, WI, USA.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2019 Mar; Vol. 597 (6), pp. 1531-1551. Date of Electronic Publication: 2019 Jan 24.
DOI: 10.1113/JP276014
Abstrakt: 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.
(© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)
Databáze: MEDLINE
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