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P. PENELA Y COLS. AN. R. ACAD. NAC. FARM

Production of reactive oxygen species (ROS) has been detected in different
cells treated with these cytokines, suggesting that ROS could mediate the
decrease in GRK2 levels observed in these experimental models of
inflammation. In fact, it has been recently described that exposure of
lymphocytes to oxidative stress results in decreased GRK2 levels in T
lymphocytes (19). Interestingly, the H2O2-induced decreases in GRK2
protein were prevented by inhibiting calpain activity, but not proteasome
function. “In vitro” proteolysis experiments show that purified m-calpain
promotes partial degradation of GRK2 in a calcium-dependent way (19). It
is tempting to suggest that calpain-mediated degradation of GRK2 could
also play a role in other situations characterized by altered calpain activity
and GRK levels, such as hypertension. Overall, these results indicate the
occurrence of different proteolytic pathways for GRK2 down-regulation
(proteasome- and calpain dependent). How these mechanisms are activated
and contribute to the control of GRK2 stability in a given cell type and
physiological condition is an interesting area of future research.

GRK2 AND INFLAMMATORY DISORDERS

GRK2, which is highly expressed in different cellular types of the
immune system, emerges as an important regulator of the immune cell
responses during inflammation. GRK2 phosphorylates manifold
chemokine receptors such as CCR5, CCR2b, CXCR4, CXCR2 and
chemotactic receptors for substance P, S1P or formyl-peptide, responsible
of leukocyte trafficking to the inflammatory foci, T cell egression from
lymphoid organs, leukocyte activation or proliferation (6). Interestingly, a
decrease of GRK2 protein expression (~55%) and kinase activity was
found in peripheral blood mononuclear cells of patients with rheumatoid
arthritis (RA), as compared with kinase levels in healthy subjects (20). The
decline of GRK2 is a direct consequence of the pathology as demonstrated
in animal models of experimental arthritis (21), which specifically show a
reduction in GRK2 levels in splenocytes and mesenteric lymph node cells.
Down-regulation of GRKs in immune cells during inflammation may
represent initially an adaptive mechanism to facilitate cell response, but
chronic GRK2 down-regulation can lead to an aberrant inflammatory

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