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Physiological changes in GRK2 regulate CCL2‐induced signaling to ERK1/2 and Akt but not to MEK1/2 and calcium
Author(s) -
Kleibeuker Wendy,
JuradoPueyo Maria,
Murga Cristina,
Eijkelkamp Niels,
Mayor Jr Federico,
Heijnen Cobi J.,
Kavelaars Annemieke
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05023.x
Subject(s) - beta adrenergic receptor kinase , g protein coupled receptor kinase , microbiology and biotechnology , protein kinase b , phosphorylation , chemistry , signal transduction , biology , g protein coupled receptor
G protein‐coupled receptor (GPCR) kinase 2 (GRK2) regulates G protein‐coupled receptor signaling via agonist‐induced receptor phosphorylation and desensitization. GRK2 can also modulate cellular activation by interacting with downstream signaling molecules. The intracellular GRK2 level changes during inflammatory conditions. We investigated how IL‐1β‐induced changes in endogenous GRK2 expression influence chemokine receptor signaling in primary astrocytes. Culturing astrocytes with IL‐1β for 24 h induced a 2–3‐fold increase in GRK2 and decreased C–C chemokine ligand 2 (CCL2)‐induced ERK1/2 activation. Conversely, the 45% decrease in GRK2 expression in astrocytes from GRK2+/− animals resulted in a more pronounced CCL2‐induced ERK1/2 phosphorylation. Increased GRK2 inhibited CCL2‐induced Akt phosphorylation at Thr308 and Ser473 as well as pPDK‐1 translocation. In contrast, altered GRK2 levels did not change the CCL2‐induced increase in intracellular calcium or MEK1/2 phosphorylation. These data suggest that altered GRK2 expression modulates chemokine signaling downstream of the receptor. We found that GRK2 kinase activity was not required to decrease chemokine‐induced ERK1/2 phosphorylation, whereas regulation of CCL2‐induced Akt phosphorylation did require an active GRK2 kinase domain. Collectively, these data suggest that changes in endogenous GRK2 expression in primary astrocytes regulate chemokine receptor signaling to ERK1/2 and to PDK‐1‐Akt downstream of receptor coupling via kinase‐dependent and kinase‐independent mechanisms, respectively.