ArticleCell communication and signaling : CCS2013
GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility.
Article in Cell communication and signaling : CCS, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 73 citations in OpenAlex.
- Reversing cardiac hypertrophy and heart failure using a cardiac targeting peptide linked to miRNA106a.Clinical and translational medicine · 2025Article
- Baicalin Prevents Chronic β-AR Agonist-Induced Heart Failure via Preventing Oxidative Stress and Overactivation of the NADPH Oxidase NOX2.Journal of cellular and molecular medicine · 2025Article
- GRK2-mediated AKT activation controls cell cycle progression and G2 checkpoint in a p53-dependent manner.Cell death discovery · 2024Article
- Inside the Biology of the β3-Adrenoceptor.Biomolecules · 2024Review
- Status of βReviews in cardiovascular medicine · 2023Review
- Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.Biochemical Society transactions · 2023Review
- Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for learning and memory.Science signaling · 2023Article
- Comparative Study of Elabela and Apelin on Apelin Receptor Activation Through β-Arrestin Recruitment.Molecular biotechnology · 2023Article
- GRK2 in cardiovascular disease and its potential as a therapeutic target.Journal of molecular and cellular cardiology · 2022Review
- The density of crown-like structures in epicardial adipose tissue could play a role in cardiovascular diseases.Eating and weight disorders : EWD · 2022Article
- Reversing Cardiac Hypertrophy at the Source Using a Cardiac Targeting Peptide Linked to miRNA106a: Targeting Genes That Cause Cardiac Hypertrophy.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling.International journal of molecular sciences · 2022Article
- GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone.World journal of cardiology · 2022Article
- Compartmentalized cAMP signaling in cardiac ventricular myocytes.Cellular signalling · 2022Review
- GTPγS Assay for Measuring Agonist-Induced Desensitization of Two Human Polymorphic AlphaMethods in molecular biology (Clifton, N.J.) · 2022Article
- Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart.Open life sciences · 2022Article
- Heart failure in diabetes.Metabolism: clinical and experimental · 2021Review
- Review
- GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.BMC biology · 2021Article
- Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure.ESC heart failure · 2020Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
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Abstract
backgroundβ1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF).
resultsWe crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular "brake" that PDE4D poses on β2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed.
conclusionsGRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.
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