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Vol. 62, Issue 2, 379-388, August 2002

Oxidative Stress Decreases G Protein-Coupled Receptor Kinase 2 in Lymphocytes via a Calpain-Dependent Mechanism

Maria Stella Lombardi, Annemieke Kavelaars, Petronila Penela, Elisabeth J. Scholtens, Marta Roccio, Reinhold E. Schmidt, Manfred Schedlowski, Federico Mayor, Jr., and Cobi J. Heijnen

Department of Immunology, Laboratory of Psychoneuroimmunology, University Medical Center, Utrecht, The Netherlands (M.S.L., A.K., E.J.S., M.R., C.J.H.); Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autonóma de Madrid, Universidad Autonóma, Madrid, Spain (P.P., F.M.); Department of Clinical Immunology, Hannover Medical School, Hannover, Germany (R.E.S.); and Department of Medical Psychology, Medical Faculty, University of Essen, Essen, Germany (M.S.)

G protein-coupled receptor kinase (GRK) 2 plays a crucial role in regulating the extent of desensitization and resensitization of G protein-coupled receptors (GPCRs). We have shown that the expression level of GRK2 in lymphocytes decreases during inflammatory diseases such as arthritis. Reactive oxygen species play an important role in a variety of inflammatory conditions, including arthritis. We demonstrate herein that oxidative stress, induced by exposure of lymphocytes to H2O2, results in a 50% reduction in GRK2 protein levels and GRK activity with no changes in mRNA expression. Treatment of lymphocytes with the tyrosine kinase inhibitor genistein partially reverses the effect of H2O2 on GRK2 levels, although we did not detect direct tyrosine phosphorylation of GRK2. Inhibition of the nonproteasomal protease calpain by calpeptin can prevent the H2O2-induced GRK2 decrease. In vitro experiments confirm that GRK2 is partially digested by m-calpain in a calcium-dependent way. Functionally, H2O2-induced decrease in GRK2 levels is associated with an ~70% decrease in agonist-induced beta 2-adrenergic receptor sequestration. We describe oxidative stress as a novel mechanism for regulation of the intracellular level of GRK2 during inflammatory processes. Moreover, our data demonstrate that oxidative stress may change the functioning of GPCRs via calpain-dependent regulation of GRK2 levels.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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