RT Journal Article
SR Electronic
T1 Oxidative Stress Decreases G Protein-Coupled Receptor Kinase 2 in Lymphocytes via a Calpain-Dependent Mechanism
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 379
OP 388
DO 10.1124/mol.62.2.379
VO 62
IS 2
A1 Maria Stella Lombardi
A1 Annemieke Kavelaars
A1 Petronila Penela
A1 Elisabeth J. Scholtens
A1 Marta Roccio
A1 Reinhold E. Schmidt
A1 Manfred Schedlowski
A1 Federico Mayor, Jr.
A1 Cobi J. Heijnen
YR 2002
UL http://molpharm.aspetjournals.org/content/62/2/379.abstract
AB 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 bym-calpain in a calcium-dependent way. Functionally, H2O2-induced decrease in GRK2 levels is associated with an ∼70% decrease in agonist-induced β2-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.