G-protein-coupled receptors as signaling targets for antiplatelet therapy.
Platelet G protein-coupled receptors (GPCRs) initiate and reinforce platelet activation and thrombus formation. The clinical utility of antagonists of the P2Y(12) receptor for ADP suggests that other GPCRs and their intracellular signaling pathways may represent viable targets for novel antiplatelet agents. For example, thrombin stimulation of platelets is mediated by 2 protease-activated receptors (PARs), PAR-1 and PAR-4. Signaling downstream of PAR-1 or PAR-4 activates phospholipase C and protein kinase C and causes autoamplification by production of thromboxane A(2), release of ADP, and generation of more thrombin. In addition to ADP receptors, thrombin and thromboxane A(2) receptors and their downstream effectors-including phosphoinositol-3 kinase, Rap1b, talin, and kindlin-are promising targets for new antiplatelet agents. The mechanistic rationale and available clinical data for drugs targeting disruption of these signaling pathways are discussed. The identification and development of new agents directed against specific platelet signaling pathways may offer an advantage in preventing thrombotic events while minimizing bleeding risk.
Smyth
Susan S
SS
Veterans Affairs Medical Center, Department of Medicine, Physiology, and Pharmacology, University of Kentucky, Lexington, KY, USA. susansmyth@uky.edu
Woulfe
Donna S
DS
Weitz
Jeffrey I
JI
Gachet
Christian
C
Conley
Pamela B
PB
Goodman
Shaun G
SG
Roe
Matthew T
MT
Kuliopulos
Athan
A
Moliterno
David J
DJ
French
Patricia A
PA
Steinhubl
Steven R
SR
Becker
Richard C
RC
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015195:Drug Design; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000097:blood; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000378:metabolism; D013931:Thromboxanes / Q000378:metabolism
C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D000244:Adenosine Diphosphate; D013917:Thrombin; C112908:protease-activated receptor 4