{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T15:41:33Z","timestamp":1778600493185,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T00:00:00Z","timestamp":1579132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005496","name":"American Foundation for Pharmaceutical Education","doi-asserted-by":"publisher","award":["333325 FY2017"],"award-info":[{"award-number":["333325 FY2017"]}],"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":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone via both G proteins and the adapter protein \u03b2arrestin1, which binds the receptor following its phosphorylation by GPCR-kinases (GRKs) to initiate G protein-independent signaling. \u03b2-adrenergic receptors (ARs) also induce aldosterone production in AZG cells. Herein, we investigated whether GRK2 or GRK5, the two major adrenal GRKs, is involved in the catecholaminergic regulation of AngII-dependent aldosterone production. In human AZG (H295R) cells in vitro, the \u03b2AR agonist isoproterenol significantly augmented both AngII-dependent aldosterone secretion and synthesis, as measured by the steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA inductions. Importantly, GRK2, but not GRK5, was indispensable for the \u03b2AR-mediated enhancement of aldosterone in response to AngII. Specifically, GRK2 inhibition with Cmpd101 abolished isoproterenol\u2019s effects on AngII-induced aldosterone synthesis\/secretion, whereas the GRK5 knockout via CRISPR\/Cas9 had no effect. It is worth noting that these findings were confirmed in vivo, since rats overexpressing GRK2, but not GRK5, in their adrenals had elevated circulating aldosterone levels compared to the control animals. However, treatment with the \u03b2-blocker propranolol prevented hyperaldosteronism in the adrenal GRK2-overexpressing rats. In conclusion, GRK2 mediates a \u03b2AR-AT1R signaling crosstalk in the adrenal cortex leading to elevated aldosterone production. This suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems at the level of the adrenal cortex and that its inhibition might be therapeutically advantageous in hyperaldosteronism-related conditions.<\/jats:p>","DOI":"10.3390\/ijms21020574","type":"journal-article","created":{"date-parts":[[2020,1,17]],"date-time":"2020-01-17T04:14:41Z","timestamp":1579234481000},"page":"574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["GRK2-Mediated Crosstalk Between \u03b2-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo"],"prefix":"10.3390","volume":"21","author":[{"given":"Celina","family":"Pollard","sequence":"first","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Ghandour","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Cora","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"Perez","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Parker","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Desimine","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelby","family":"Wertz","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janelle","family":"Pereyra","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krysten","family":"Ferraino","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jainika","family":"Patel","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.4330\/wjc.v9.i3.200","article-title":"Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure 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