title: A peptide of the RGS domain of GRK2 binds and inhibits Gα(q) to suppress pathological cardiac hypertrophy and dysfunction.
abstract: G protein-coupled receptor (GPCR) kinases (GRKs) play a critical role in cardiac function by regulating GPCR activity. GRK2 suppresses GPCR signaling by phosphorylating and desensitizing active GPCRs, and through protein-protein interactions that uncouple GPCRs from their downstream effectors. Several GRK2 interacting partners, including Gα(q), promote maladaptive cardiac hypertrophy, which leads to heart failure, a leading cause of mortality worldwide. The regulator of G protein signaling (RGS) domain of GRK2 interacts with and inhibits Gα(q) in vitro. We generated TgβARKrgs mice with cardiac-specific expression of the RGS domain of GRK2 and subjected these mice to pressure overload to trigger adaptive changes that lead to heart failure. Unlike their nontransgenic littermate controls, the TgβARKrgs mice exhibited less hypertrophy as indicated by reduced left ventricular wall thickness, decreased expression of genes linked to cardiac hypertrophy, and less adverse structural remodeling. The βARKrgs peptide, but not endogenous GRK2, interacted with Gα(q) and interfered with signaling through this G protein. These data support the development of GRK2-based therapeutic approaches to prevent hypertrophy and heart failure.
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Schumacher
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lieu
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. walter.koch@temple.edu.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains
chemical_list: D010455:Peptides; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11