title: Differential roles of integrins alpha2beta1 and alphaIIbbeta3 in collagen and CRP-induced platelet activation.
abstract: Collagen and collagen-related peptide (CRP) activate platelets by interacting with glycoprotein (GP)VI. In addition, collagen binds to integrin alpha2beta1 and possibly to other receptors. In this study, we have compared the role of integrins alpha2beta1 and alphaIIbbeta3 in platelet activation induced by collagen and CRP. Inhibitors of ADP and thromboxane A2 (TxA2) substantially attenuated collagen-induced platelet aggregation and dense granule release, whereas CRP-induced responses were only partially inhibited. Under these conditions, a proportion of platelets adhered to the collagen fibres resulting in dense granule release and alphaIIbbeta3 activation. This adhesion was substantially mediated by alpha2beta1. The alphaIIbbeta3 antagonist lotrafiban potentiated CRP-induced dense granule release, suggesting that alphaIIbbeta3 outside-in signalling may attenuate GPVI signals. By contrast, lotrafiban inhibited collagen-induced dense granule release. These results emphasise the differential roles of alpha2beta1 and alphaIIbbeta3 in platelet activation induced by collagen and CRP. Further, they show that although ADP and TxA2 greatly facilitate collagen-induced platelet activation, collagen can induce full activation of those platelets to which it binds in the absence of these mediators, via a mechanism that is dependent on adhesion to alpha2beta1.
authors.affiliation: Department of Pharmacology, University of Oxford, UK. gej1000@cam.ac.uk
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Jarvis
authors.forename: Denise
authors.initials: D
authors.lastname: Best
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology* / Q000502:physiology; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D054641:Dual Specificity Phosphatase 2; D006801:Humans; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019007:P-Selectin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013928:Thromboxane A2 / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D038982:Integrin alpha2beta1; D019007:P-Selectin; D010455:Peptides; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D001569:Benzodiazepines; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D003094:Collagen; D054648:Protein Phosphatase 2; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases; C412702:lotrafiban