ArticleJournal of the American Heart Association2013
Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction.
Article in Journal of the American Heart Association, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 60 citations in OpenAlex.
- CaThe Journal of physiology · 2026Article
- Multi-omics analysis reveals sex-specific etiology of human muscle weakness following musculoskeletal injury.BMC medicine · 2026Article
- Autonomic dysregulation and atrial arrhythmias.American journal of physiology. Cell physiology · 2025Review
- 14-3-3 promotes sarcolemmal expression of cardiac CaProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.NPJ Regenerative medicine · 2025Article
- Rad-mediated inhibition of CaThe Journal of physiology · 2024Article
- Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac CaBMC biology · 2024Article
- α1Journal of the American Heart Association · 2024Article
- Rad protein: An essential player in L-type Ca2+ channel localization and modulation in cardiomyocytes.The Journal of general physiology · 2024Article
- The C-terminus of Rad is required for membrane localization and L-type calcium channel regulation.The Journal of general physiology · 2024Article
- BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.Nature communications · 2024Article
- A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.The Journal of clinical investigation · 2024Article
- Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.Research square · 2023Article
- Compartmentalized cAMP signalling and control of cardiac rhythm.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Inactivation influences the extent of inhibition of voltage-gated CaFrontiers in physiology · 2023Article
- Sympathetic Nervous System Regulation of Cardiac Calcium Channels.Handbook of experimental pharmacology · 2023Article
- Cardiac CaNature cardiovascular research · 2022Article
- Rad regulation of CaNature cardiovascular research · 2022Article
- Adrenergic Regulation of Calcium Channels in the Heart.Annual review of physiology · 2022Review
- L-type channel inactivation balances the increased peak calcium current due to absence of Rad in cardiomyocytes.The Journal of general physiology · 2021Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundThe 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. METHODS AND
resultsVentricular 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 working hearts, similar results were obtained; chiefly, +dP/dt was elevated at baseline and developed pressure was relatively nonresponsive to acute β-adrenergic receptor stimulation. In single cells, at subphysiological frequencies, nonstimulated calmodulin-dependent protein kinase-sensitive calcium release is observed. Remarkably, Rad(-/-) hearts did not show hypertrophic growth despite elevated levels of diastolic calcium.
conclusionsThis study demonstrates that the depletion of Rad GTPase is equivalent to sympathomimetic β-adrenergic receptor, without stimulating cardiac hypertrophy. Thus, targeting Rad GTPase is a novel potential therapeutic target for Ca(2+)-homeostasis-driven positive inotropic support of the heart.
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