Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction

Journal of the American Heart Association
Janet R ManningJonathan Satin

Abstract

The small GTPase Rad is a negative regulator of voltage-dependent L-type calcium channel current (ICaL); however, the effects of Rad ablation on cardiomyocyte function are unknown. The objective of this study is to test the hypothesis that Rad-depletion causes positive inotropic effects without inducing cardiac hypertrophy. Ventricular myocytes from adult Rad(-/-) mice were isolated and evaluated by patch-clamp recordings for I(Ca,L) and action potentials, Ca(2+) transients, and sarcomere shortening. Maximum I(CaL) is elevated in Rad(-/-) (maximal conductance 0.35 ± 0.04 picoSiemens/picoFarad (pS/pF) wild-type; 0.61 ± 0.14 pS/pF Rad(-/-)), decay kinetics are faster, and I(Ca,L) activates at lower voltages (activation midpoint -7.2 ± 0.6 wild-type; -11.7 ± 0.9 Rad(-/-)) mimicking effects of β-adrenergic receptor stimulation. Diastolic and twitch calcium are elevated in Rad(-/-) (F340/380: 1.03 diastolic and 0.35 twitch for wild-type; 1.47 diastolic and 0.736 twitch for Rad(-/-)) and sarcomere shortening is enhanced (4.31% wild-type; 14.13% Rad(-/-)) at lower pacing frequencies. Consequentially, frequency-dependence of Ca(2+) transients is less in Rad(-/-), and the frequency dependence of relaxation is also blunted. In isolated w...Continue Reading

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Citations

Mar 17, 2015·Pflügers Archiv : European journal of physiology·Donald BeqollariRoger A Bannister
Nov 1, 2016·Journal of Cardiovascular Translational Research·Bryana M LevitanJonathan Satin
Dec 14, 2017·Acta Physiologica·U MezaR A Bannister
Oct 19, 2017·The Journal of Cell Biology·Stephanie O AgbuKathryn V Anderson
May 31, 2019·The Journal of Biological Chemistry·Brooke M AhernJonathan Satin
Nov 11, 2014·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Satomi Adachi-Akahane
Jan 29, 2020·Nature·Xiaohan Wang, Richard W Tsien
Sep 16, 2015·American Journal of Physiology. Heart and Circulatory Physiology·Janet R ManningJonathan Satin
Jan 13, 2015·Science China. Life Sciences·Zafir BuraeiJian Yang
Feb 9, 2021·Journal of Molecular and Cellular Cardiology·Bryana M LevitanJonathan Satin
Feb 10, 2021·Proceedings of the National Academy of Sciences of the United States of America·Silvia G Del VillarRose E Dixon
May 19, 2021·Proceedings of the National Academy of Sciences of the United States of America·Moshe KatzNathan Dascal
Jul 15, 2021·Cell Calcium·Daniel R MirandaRoger A Bannister
Jul 17, 2021·The Journal of General Physiology·Brooke M AhernJonathan Satin

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Methods Mentioned

BETA
GTPases

Software Mentioned

DataquestART

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