6533b831fe1ef96bd1299072

RESEARCH PRODUCT

The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors.

Guido IaccarinoAngela Serena MaioneTrimarco BrunoMichele CiccarelliDaniela SorrientoGaetano SantulliMaddalena Illario

subject

0301 basic medicineG-Protein-Coupled Receptor Kinase 5MalecalmodulinMutantWistarPlasma protein binding030204 cardiovascular system & hematologyCatalysilcsh:ChemistryPhenylephrine0302 clinical medicineRats Inbred SHRMyocytes Cardiaclcsh:QH301-705.5SpectroscopybiologyChemistrycardiac hypertrophyNFATComputer Science Applications1707 Computer Vision and Pattern RecognitionGeneral MedicineLeft VentricularComputer Science ApplicationsCell biologycardiac hypertrophy; transcription factors; calmodulin; GRKGRKHypertrophy Left VentricularCardiacProtein BindingInbred SHRCalmodulinCalmodulin; Cardiac hypertrophy; GRK; Transcription factors; Animals; Binding Sites; Calmodulin; Cell Line; G-Protein-Coupled Receptor Kinase 5; GATA4 Transcription Factor; Hypertrophy Left Ventricular; Male; Myocytes Cardiac; NFATC Transcription Factors; Phenylephrine; Protein Binding; Rats; Rats Inbred SHR; Rats Wistar; Catalysis; Molecular Biology; Spectroscopy; Computer Science Applications1707 Computer Vision and Pattern Recognition; Physical and Theoretical Chemistry; Organic Chemistry; Inorganic ChemistryCatalysisArticleCell LineInorganic Chemistry03 medical and health sciencesG-Protein-Coupled Receptor Kinase 5transcription factorsAnimalsPhysical and Theoretical ChemistryRats WistarTranscription factorMolecular BiologyG protein-coupled receptor kinaseMyocytesBinding SitesNFATC Transcription FactorsOrganic ChemistryHypertrophyNFATC Transcription FactorsGATA4 Transcription FactorRats030104 developmental biologylcsh:Biology (General)lcsh:QD1-999biology.proteinTranscription factor

description

We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE). These results were confirmed in vivo in spontaneously hypertensive rats (SHR), in which intramyocardial adenovirus-mediated gene transfer of GRK5-NT reduced both wall thickness and ventricular mass by modulating NFAT and GATA-4 activity. To further verify in vitro the contribution of calmodulin in linking GRK5-NT to the NFAT/GATA-4 pathway, we examined the effects of a mutant of GRK5 (GRK5-NTPB), which is not able to bind calmodulin. When compared to GRK5-NT, GRK5-NTPB did not modify PE-induced NFAT and GATA-4 activation. In conclusion, this study identifies a double effect of GRK5-NT in the inhibition of LVH that is based on the regulation of multiple transcription factors through means of different mechanisms and proposes the amino-terminal sequence of GRK5 as a useful prototype for therapeutic purposes.

yearjournalcountryeditionlanguage
2018-03-15International journal of molecular sciences
10.3390/ijms19030861https://pubmed.ncbi.nlm.nih.gov/29543709