Kistrin, an integrin antagonist, blocks endocytosis of fibrinogen into guinea pig megakaryocyte and platelet alpha-granules.
Recent data indicate that megakaryocyte/platelet alpha-granule fibrinogen is endocytosed from plasma. Because fibrinogen is the major platelet protein present in high concentrations in alpha-granules, fibrinogen uptake into alpha-granules may occur via specific receptors. In that cells of the megakaryocyte/platelet lineage contain two integrins--alpha IIb beta 3 (GP IIb-IIIa) and the vitronectin receptor (alpha v beta 3)--that can bind fibrinogen, one or both of these receptors may mediate the endocytic uptake of fibrinogen. To test this hypothesis, we examined the effect of Kistrin, an RGD-containing protein purified from the venom of Agkistrodon rhodostoma that inhibits fibrinogen binding to human platelet receptors, on endocytosis of fibrinogen by megakaryocytes and platelets. Continuous intravenous infusion of kistrin into guinea pigs (200 micrograms/h) over a 24-h period inhibited collagen-induced platelet aggregation. When biotinylated fibrinogen was injected intravenously into animals receiving Kistrin, megakaryocytes failed to endocytose the labeled fibrinogen. Endocytosis of fibrinogen into platelets was also inhibited in these animals. In contrast, platelets and megakaryocytes obtained from sham-infused control animals contained the injected biotinylated fibrinogen. We conclude that, in addition to the well-known extracellular function of cell adhesion, integrins can also act as receptors that mediate endocytosis of exogenous proteins and incorporate them into regulated secretory granules.
Handagama
P
P
Department of Pathology, University of California, San Francisco 94143-0506.
Bainton
D F
DF
Jacques
Y
Y
Conn
M T
MT
Lazarus
R A
RA
Shuman
M A
MA
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003435:Crotalid Venoms / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004705:Endocytosis / Q000187:drug effects*; D005340:Fibrinogen / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D010455:Peptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*
D003435:Crotalid Venoms; D005343:Fibrinolytic Agents; D016023:Integrins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C067623:kistrin; D005340:Fibrinogen