A complementary role for tetraspanin superfamily member CD151 and ADP purinergic P2Y12 receptor in platelets

Mohammed Makkawi; Fatemeh Moheimani; Raed Alserihi; David Howells; Mark Wright; Leonie Ashman; Denise E. Jackson

doi:10.1160/TH14-11-0967

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2015; 114(05): 1004-1019
DOI: 10.1160/TH14-11-0967

Cellular Haemostasis and Platelets

Schattauer GmbH

A complementary role for tetraspanin superfamily member CD151 and ADP purinergic P2Y₁₂ receptor in platelets

Mohammed Makkawi

¹Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, RMIT University, Victoria, Australia

²Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia

,

Fatemeh Moheimani

¹Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, RMIT University, Victoria, Australia

,

Raed Alserihi

¹Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, RMIT University, Victoria, Australia

,

David Howells

³Neuroscience Laboratory, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia

,

Mark Wright

⁴Department of Immunology, Monash University, Melbourne, Victoria, Australia

,

Leonie Ashman

⁵School of Biomedical Sciences,, University of Newcastle, Newcastle, New South Wales, Australia

,

Denise E. Jackson

¹Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, RMIT University, Victoria, Australia

› Institutsangaben

Abstract

Summary

P2Y₁₂ receptor is required for sustained activation of integrin α_llbβ₃, irreversible platelet aggregation and thrombus stabilisation. Tetraspanin superfamily member CD151 associates with integrin aNbp3 and plays critical roles in regulation of thrombus growth and stability in vivo. The possible functional relationship between P2Y₁₂ and CD151 in a molecular cluster in platelets may affect thrombus formation. Hence our aim was to investigate the physical and functional requirements for this association in platelets. Our investigations reveal a specific and constitutive association between CD151 and P2Y₁₂ receptor in human platelets shown by immunoprecipitation/western blot studies and by flow cytometry. Specifically, the prominent association involves CD151 with P2Y₁₂ oligomers, and to a lesser extent P2Y₁₂ monomers. This association is not altered by platelet aggregation induced by different agonists. There is also a distinct complex of tetraspanin CD151 with ADP purinergic receptor P2Y₁₂ but not P2Y₁. P2Y₁₂ oligomer interaction with CD151 is selective as compared to other tetraspanins. To investigate the functional relationship between these receptors in platelets we used wild-type or CD151 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. CD151 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, in PAR-4 and collagen-mediated platelet aggregation, platelet spreading on fibrinogen and without restricting cAMP inhibition. Clopidogrel treated CD151 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise ex vivo and in vivo. These studies demonstrate a complementary role between CD151 and P2Y₁₂ receptor in platelets in regulating thrombus growth and stability.

Keywords

Platelets - CD151 - mice - clopidogrel - purinergic P2Y12

Volltext

Referenzen

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