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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

Institute for Surgical Research, Rikshospitalet-Radiumhospitalet Medical Center and University of Oslo, Norway (L.E.V., T.A., M.S.A., H.A.); Department of Pharmacology, University of Oslo, Norway (K.W.A., G.Ø.A., F.O.L., T.S., J.-B.O.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., W.J.K.); and Department of Medicine, Duke University Medical Center, Durham, North Carolina (N.J.F.)

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 -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, ₁-adrenergic, and 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 (IC₅₀ for GRK3, 5 ± 0.7 pmol/mg of protein; EC₅₀ for GRK3ct, 2 ± 0.2 pmol/mg of protein). The ₁-adrenergic receptor was also a preferred substrate of GRK3 (IC₅₀,7 ± 0.4 pmol/mg of protein). GRK2 lacked efficacy at both endothelin and ₁-adrenergic receptors despite massive overexpression. On the contrary, both GRK2ct and GRK3ct enhanced ₁-adrenergic receptor-induced cAMP production with comparable potencies. However, the potency of GRK3ct at 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 ₁-adrenergic receptors, whereas GRK3 may play important roles in regulation of cardiac growth and hypertrophy by selectively controlling endothelin and ₁-adrenergic receptors.

Address correspondence to: Dr. Håvard Attramadal, Institute for Surgical Research, A3.1013, Rikshospitalet-Radiumhospitalet Medical Center, Sognsvannsveien 20, N-0027 Oslo, Norway. E-mail: havard.attramadal{at}medisin.uio.no

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