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ADP-induced platelet activation
1Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Insights
Adenosine diphosphate (ADP) is crucial for platelet aggregation in thrombosis. This review details efforts to understand ADP-receptor mechanisms and develop targeted anti-platelet drugs.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Platelet activation by adenosine diphosphate (ADP) is central to hemostasis and arterial thrombosis, implicated in cardiovascular events like myocardial infarction and stroke.
- ADP mediates platelet aggregation, shape change, secretion, calcium mobilization, and adenylyl cyclase inhibition, but the specific ADP-receptor remains elusive.
- Understanding ADP-induced platelet responses is critical for developing effective anti-platelet therapies.
Purpose of the Study:
- To review advancements in identifying the ADP-receptor protein.
- To elucidate the signal transduction mechanisms underlying ADP-induced platelet activation.
- To explore strategies for designing novel drugs that selectively target the ADP-receptor or its downstream pathways.
Main Methods:
- Review of recent contributions from multidisciplinary research (chemistry, biochemistry, cell biology, pharmacology, molecular biology, clinical investigation).
- Analysis of efforts to purify and clone the ADP-receptor.
- Evaluation of newly developed drugs that selectively inhibit ADP-induced platelet responses.
Main Results:
- Significant progress has been made in understanding ADP-induced platelet responses, despite ongoing controversies and challenges in receptor identification.
- New classes of drugs have been developed, including those that mimic ADP and selectively target the ADP-receptor, and others that inhibit ADP-induced activation ex vivo.
- These advancements provide a foundation for innovative therapeutic strategies.
Conclusions:
- Continued research is essential to fully characterize the ADP-receptor and its signaling pathways.
- Selective inhibition of ADP-mediated platelet activation holds therapeutic promise for preventing thrombotic events.
- Developing targeted anti-platelet drugs is a key strategy for managing cardiovascular diseases.
Abstract:
Platelet activation is central to the pathogenesis of hemostasis and arterial thrombosis. Platelet aggregation plays a major role in acute coronary artery diseases, myocardial infarction, unstable angina, and stroke. ADP is the first known and an important agonist for platelet aggregation. ADP not only causes primary aggregation of platelets but is also responsible for the secondary aggregation induced by ADP and other agonists. ADP also induces platelet shape change, secretion from storage granules, influx and intracellular mobilization of Ca2+, and inhibition of stimulated adenylyl cyclase activity. The ADP-receptor protein mediating ADP-induced platelet responses has neither been purified nor cloned. Therefore, signal transduction mechanisms underlying ADP-induced platelet responses either remain uncertain or less well understood. Recent contributions from chemists, biochemists, cell biologists, pharmacologists, molecular biologists, and clinical investigators have added considerably to and enhanced our knowledge of ADP-induced platelet responses. Although considerable efforts have been directed toward identifying and cloning the ADP-receptor, these have not been completely successful or without controversy. Considerable progress has been made toward understanding the mechanisms of ADP-induced platelet responses but disagreements persist. New drugs that do not mimic ADP have been found to inhibit fairly selectively ADP-induced platelet activation ex vivo. Drugs that mimic ADP and selectively act at the platelet ADP-receptor have been designed, synthesized, and evaluated for their therapeutic efficacy to block selectively ADP-induced platelet responses. This review examines in detail the developments that have taken place to identify the ADP-receptor protein and to better understand mechanisms underlying ADP-induced platelet responses to develop strategies for designing innovative drugs that block ADP-induced platelet responses by acting selectively at the ADP-receptor and/or by selectively interfering with components of ADP-induced platelet activation mechanisms.