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Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases
Ist Teil von
The Journal of biological chemistry, 1994-01, Vol.269 (2), p.1125-1130
Ort / Verlag
Bethesda, MD: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
1994
Quelle
MEDLINE
Beschreibungen/Notizen
The thrombin receptor, a member of the seven membrane-spanning superfamily of G-protein coupled receptors, is activated by
an irreversible proteolytic mechanism, but signaling by activated thrombin receptors shuts off soon after receptor activation.
This shut-off mechanism is thought to be required for concentration-dependent responses to thrombin and an important determinant
of the cell's sensitivity to thrombin. We report that the thrombin receptor is rapidly phosphorylated upon activation, consistent
with the action of a G-protein-coupled receptor kinase. Moreover, the G-protein coupled receptor kinase BARK2 (beta-adrenergic
receptor kinase 2) blocked signaling by thrombin receptors coexpressed in Xenopus oocytes. In this system, rhodopsin kinase
was inactive and BARK1 was markedly less effective than BARK2. Thrombin receptor mutants which lacked potential serine and
threonine phosphorylation sites in the receptor's cytoplasmic tail were insensitive to inhibition by exogenous BARK2 but did
confer concentration-dependent responses to thrombin. Our studies demonstrate that a G-protein coupled receptor kinase can
shut off thrombin receptor signaling but that additional mechanism(s) for terminating signaling exist. These studies also
reveal functional specificity among G-protein coupled receptor kinases in a novel in vivo reconstitution system and show that
heterologous expression of these kinases can be used to manipulate cellular responsiveness.