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Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function.

Publication ,  Journal Article
Vinge, LE; Andressen, KW; Attramadal, T; Andersen, GØ; Ahmed, MS; Peppel, K; Koch, WJ; Freedman, NJ; Levy, FO; Skomedal, T; Osnes, J-B; Attramadal, H
Published in: Mol Pharmacol
September 2007

The closely related G protein-coupled receptor kinases GRK2 and GRK3 are both expressed in cardiac myocytes. Although GRK2 has been extensively investigated in terms of regulation of cardiac beta-adrenergic receptors, the substrate specificities of the two GRK isoforms at G protein-coupled receptors (GPCR) are poorly understood. In this study, the substrate specificities of GRK2 and GRK3 at GPCRs that control cardiac myocyte function were determined in fully differentiated adult cardiac myocytes. Concentration-effect relationships of GRK2, GRK3, and their respective competitive inhibitors, GRK2ct and GRK3ct, at endogenous endothelin, alpha(1)-adrenergic, and beta(1)-adrenergic receptor-generated responses in cardiac myocytes were achieved by adenovirus gene transduction. GRK3 and GRK3ct were highly potent and efficient at the endothelin receptors (IC(50) for GRK3, 5 +/- 0.7 pmol/mg of protein; EC(50) for GRK3ct, 2 +/- 0.2 pmol/mg of protein). The alpha(1)-adrenergic receptor was also a preferred substrate of GRK3 (IC(50),7 +/- 0.4 pmol/mg of protein). GRK2 lacked efficacy at both endothelin and alpha(1)-adrenergic receptors despite massive overexpression. On the contrary, both GRK2ct and GRK3ct enhanced beta(1)-adrenergic receptor-induced cAMP production with comparable potencies. However, the potency of GRK3ct at beta(1)-adrenergic receptors was at least 20-fold lower than that at endothelin receptors. In conclusion, this study demonstrates distinct substrate specificities of GRK2 and GRK3 at different GPCRs in fully differentiated adult cardiac myocytes. As inferred from the above findings, GRK2 may play its primary role in regulation of cardiac contractility and chronotropy by controlling beta(1)-adrenergic receptors, whereas GRK3 may play important roles in regulation of cardiac growth and hypertrophy by selectively controlling endothelin and alpha(1)-adrenergic receptors.

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Published In

Mol Pharmacol

DOI

ISSN

0026-895X

Publication Date

September 2007

Volume

72

Issue

3

Start / End Page

582 / 591

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Transduction, Genetic
  • Substrate Specificity
  • Receptors, Endothelin
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, alpha-1
  • Rats, Wistar
  • Rats
  • Pharmacology & Pharmacy
  • Myocytes, Cardiac
 

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Vinge, L. E., Andressen, K. W., Attramadal, T., Andersen, G. Ø., Ahmed, M. S., Peppel, K., … Attramadal, H. (2007). Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Mol Pharmacol, 72(3), 582–591. https://doi.org/10.1124/mol.107.035766
Vinge, Leif Erik, Kjetil W. Andressen, Toril Attramadal, Geir Øystein Andersen, Mohammed Shakil Ahmed, Karsten Peppel, Walter J. Koch, et al. “Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function.Mol Pharmacol 72, no. 3 (September 2007): 582–91. https://doi.org/10.1124/mol.107.035766.
Vinge LE, Andressen KW, Attramadal T, Andersen GØ, Ahmed MS, Peppel K, et al. Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Mol Pharmacol. 2007 Sep;72(3):582–91.
Vinge, Leif Erik, et al. “Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function.Mol Pharmacol, vol. 72, no. 3, Sept. 2007, pp. 582–91. Pubmed, doi:10.1124/mol.107.035766.
Vinge LE, Andressen KW, Attramadal T, Andersen GØ, Ahmed MS, Peppel K, Koch WJ, Freedman NJ, Levy FO, Skomedal T, Osnes J-B, Attramadal H. Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Mol Pharmacol. 2007 Sep;72(3):582–591.

Published In

Mol Pharmacol

DOI

ISSN

0026-895X

Publication Date

September 2007

Volume

72

Issue

3

Start / End Page

582 / 591

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Transduction, Genetic
  • Substrate Specificity
  • Receptors, Endothelin
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, alpha-1
  • Rats, Wistar
  • Rats
  • Pharmacology & Pharmacy
  • Myocytes, Cardiac