{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:36:38Z","timestamp":1787160998476,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T00:00:00Z","timestamp":1587340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["09SDG2010138"],"award-info":[{"award-number":["09SDG2010138"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005496","name":"American Foundation for Pharmaceutical Education","doi-asserted-by":"publisher","award":["333325"],"award-info":[{"award-number":["333325"]}],"id":[{"id":"10.13039\/100005496","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009846","name":"Nova Southeastern University","doi-asserted-by":"publisher","award":["PFRDG 335467"],"award-info":[{"award-number":["PFRDG 335467"]}],"id":[{"id":"10.13039\/100009846","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)\/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon \u03b22-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. \u03b22AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via \u03b22AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.<\/jats:p>","DOI":"10.3390\/ijms21082868","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T04:49:38Z","timestamp":1587444578000},"page":"2868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4772-4482","authenticated-orcid":false,"given":"Jennifer","family":"Maning","sequence":"first","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"McCrink","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celina","family":"Pollard","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Desimine","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Ghandour","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Perez","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Cora","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krysten","family":"Ferraino","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Parker","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ava","family":"Brill","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6979-6575","authenticated-orcid":false,"given":"Beatrix","family":"Aukszi","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Physics, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9817-6319","authenticated-orcid":false,"given":"Anastasios","family":"Lymperopoulos","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1056\/NEJMra000050","article-title":"Aldosterone in congestive heart failure","volume":"345","author":"Weber","year":"2001","journal-title":"N. 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