Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition.
Aldosterone
/ metabolism
Animals
Apoptosis
Cell Line
G-Protein-Coupled Receptor Kinase 2
/ genetics
G-Protein-Coupled Receptor Kinase 5
/ genetics
Models, Biological
Myocytes, Cardiac
/ metabolism
Oxidative Stress
Phosphorylation
Protein Binding
Rats
Receptors, Adrenergic, beta-2
/ metabolism
Receptors, G-Protein-Coupled
/ agonists
Receptors, Mineralocorticoid
/ metabolism
Signal Transduction
/ drug effects
Transcriptional Activation
G protein-coupled estrogen receptor
G protein-coupled receptor kinase
aldosterone
cardiac myocyte
mineralocorticoid receptor
signal transduction
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
20 Apr 2020
20 Apr 2020
Historique:
received:
20
03
2020
revised:
14
04
2020
accepted:
17
04
2020
entrez:
25
4
2020
pubmed:
25
4
2020
medline:
23
1
2021
Statut:
epublish
Résumé
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 β
Identifiants
pubmed: 32326036
pii: ijms21082868
doi: 10.3390/ijms21082868
pmc: PMC7215681
pii:
doi:
Substances chimiques
Gper1 protein, rat
0
Receptors, Adrenergic, beta-2
0
Receptors, G-Protein-Coupled
0
Receptors, Mineralocorticoid
0
Aldosterone
4964P6T9RB
Grk2 protein, rat
EC 2.7.11.15
G-Protein-Coupled Receptor Kinase 2
EC 2.7.11.16
G-Protein-Coupled Receptor Kinase 5
EC 2.7.11.16
Grk5 protein, rat
EC 2.7.11.16
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : American Heart Association
ID : 09SDG2010138
Organisme : American Foundation for Pharmaceutical Education
ID : 333325
Organisme : Nova Southeastern University
ID : PFRDG 335467
Commentaires et corrections
Type : ErratumIn
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