Thrombin receptors: turning them off after turning them on.
Recent studies have helped to define the mechanisms by which thrombin activates platelets and other cells. Those studies show that the human thrombin receptor has a structure similar to other G protein-coupled receptors, but is activated by a novel mechanism in which thrombin cleaves its receptor, creating a new N-terminus that can serve as a tethered ligand. Shortly after activation, thrombin receptors become temporarily resistant to re-activation. Present evidence suggests that this loss of function is due to a combination of receptor desensitization, phosphorylation and internalization, and that recovery may involve dephosphorylation, as well as receptor recycling and the expression of newly-synthesized receptors. Together these processes provide a potent mechanism for limiting the duration of thrombin-initiated events in platelets and other thrombin-responsive vascular cells.
Department of Medicine, University of Pennsylvania, Philadelphia 19104.
L F
LF
Brass
M
M
Ahuja
E
E
Belmonte
N
N
Blanchard
S
S
Pizarro
A
A
Tarver
J A
JA
Hoxie
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D004705:Endocytosis; D005347:Fibroblasts; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D008533:Megakaryocytes / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D018179:Receptors, Thrombin / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D047428:Protein Kinase Inhibitors; D018179:Receptors, Thrombin; D011993:Recombinant Fusion Proteins; D011494:Protein Kinases; D019204:GTP-Binding Proteins