title: Nuclear translocation of cardiac G protein-Coupled Receptor kinase 5 downstream of select Gq-activating hypertrophic ligands is a calmodulin-dependent process.
abstract: G protein-Coupled Receptors (GPCRs) kinases (GRKs) play a crucial role in regulating cardiac hypertrophy. Recent data from our lab has shown that, following ventricular pressure overload, GRK5, a primary cardiac GRK, facilitates maladaptive myocyte growth via novel nuclear localization. In the nucleus, GRK5's newly discovered kinase activity on histone deacetylase 5 induces hypertrophic gene transcription. The mechanisms governing the nuclear targeting of GRK5 are unknown. We report here that GRK5 nuclear accumulation is dependent on Ca(2+)/calmodulin (CaM) binding to a specific site within the amino terminus of GRK5 and this interaction occurs after selective activation of hypertrophic Gq-coupled receptors. Stimulation of myocytes with phenylephrine or angiotensinII causes GRK5 to leave the sarcolemmal membrane and accumulate in the nucleus, while the endothelin-1 does not cause nuclear GRK5 localization. A mutation within the amino-terminus of GRK5 negating CaM binding attenuates GRK5 movement from the sarcolemma to the nucleus and, importantly, overexpression of this mutant does not facilitate cardiac hypertrophy and related gene transcription in vitro and in vivo. Our data reveal that CaM binding to GRK5 is a physiologically relevant event that is absolutely required for nuclear GRK5 localization downstream of hypertrophic stimuli, thus facilitating GRK5-dependent regulation of maladaptive hypertrophy.
authors.affiliation: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Gold
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Martini
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hullmann
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.forename: Linda
authors.initials: L
authors.lastname: Lee
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.forename: Julie
authors.initials: J
authors.lastname: Bossuyt
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006984:Hypertrophy; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D051381:Rats
chemical_list: D002147:Calmodulin; D008024:Ligands; D000804:Angiotensin II; D010656:Phenylephrine; D054774:G-Protein-Coupled Receptor Kinase 5; D043802:GTP-Binding Protein alpha Subunits, Gq-G11