A new role for the A2b adenosine receptor in regulating platelet function.
BACKGROUND
Activation of platelets is a critical component of atherothrombosis and plays a central role in the progression of unstable cardiovascular syndromes. Adenosine, acting through adenosine receptors, increases intracellular cAMP levels and inhibits platelet aggregation. The A2a adenosine receptor has already been recognized as a mediator of adenosine-dependent effects on platelet aggregation, and here we present a new role for the A2b adenosine receptor (A2bAR) in this process.


RESULTS
As compared with platelets from wild-type controls, platelets derived from A2bAR knockout mice have significantly greater ADP receptor activation-induced aggregation. Although mouse megakaryocytes and platelets express low levels of the A2bAR transcript, this gene is highly upregulated following injury and systemic inflammation in vivo. Under these conditions, A2bAR-mediated inhibition of platelet aggregation significantly increases. Our studies also identify a novel mechanism by which the A2bAR could regulate platelet aggregation; namely, ablation of the A2bAR leads to upregulated expression of the P2Y1 ADP receptor, whereas A2bAR-mediated or direct elevation of cAMP has the opposite effect. Thus, the A2bAR regulates platelet function beyond mediating the immediate effect of adenosine on aggregation.


CONCLUSIONS
Taken together, these investigations show for the first time that the platelet A2bAR is upregulated under stress in vivo, plays a significant role in regulating ADP receptor expression, and inhibits agonist-induced platelet aggregation.
Yang
D
D
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Chen
H
H
Koupenova
M
M
Carroll
S H
SH
Eliades
A
A
Freedman
J E
JE
Toselli
P
P
Ravid
K
K
D058908:Adenosine A2 Receptor Agonists; D000244:Adenosine Diphosphate / Q000097:blood*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000097:blood; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism; D005838:Genotype; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood; D043704:Receptor, Adenosine A2B / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000235:genetics; D058472:Receptors, Purinergic P2Y1; D013997:Time Factors; D015854:Up-Regulation
D058908:Adenosine A2 Receptor Agonists; D008070:Lipopolysaccharides; C546383:P2ry1 protein, mouse; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D019830:Adenosine-5'-(N-ethylcarboxamide); D000244:Adenosine Diphosphate; D000242:Cyclic AMP