Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

Abstract

Platelets are key mediators of thrombosis. Drugs that interfere with platelet activation substantially improve survival in arterial thrombotic disease. One attractive family of drug targets which has already been exploited in the development of antiplatelet agents are G-protein coupled receptors (GPCRs). Yet limitations of present antiplatelet agents, including incomplete efficacy, bleeding and drug resistance, have spurred the development of new drugs directed at alternative platelet GPCRs. Compounds that target platelet receptors including P2Y(12), protease-activated receptor-1 (PAR1), the thromboxane A(2) receptor (TP receptor), the prostaglandin receptor (EP3 receptor), and the serotonin receptor (5-HT(2A) receptor) have been identified and are in various phases of clinical development and use. Yet, improving the clinical profile of reagents targeting platelet GPCRs may not be only a matter of blocking alternative GPCRs. A more detailed understanding of GPCR function is leading to the development of pharmacophores with novel mechanisms of drug action. Identifying compounds that work by alternative mechanisms may be equally or more valuable than developing reagents targeting different GPCRs. Pharmacological concepts such as GPCR oligomerization, allosterism, and targeting GPCR-G protein interactions may ultimately provide opportunities to more effectively control platelet activation in the clinical setting. In this review, we will discuss the utility and limitations of GPCR-targeted antiplatelet therapies in clinical use and development. We will also consider emerging concepts in GPCR pharmacology that have the potential to foster the development of GPCR-targeted reagents with novel mechanisms of action and improved clinical profiles.

Protein kinase C delta contributes to increase in EP3 agonist-induced contraction in mesenteric arteries from type 2 diabetic Goto-Kakizaki rats

“…This is consistent with the results obtained in a previous study using a different vessel [61]. Multiple bands for GPCRs including EP receptors could result from oligomerization of the receptor, post-transcriptional modification of the protein or the formation of heteromers with other proteins [6,7,12,21,66]. Although the exact conformations of the EP3 receptors present in diabetic mesenteric arteries remains unclear, we think that differences in the downstream Fig.…”

Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10

“…The attenuated marginal band contraction identified in RanBP10 Ϫ/Ϫ platelets could thus be a mechanistic link between impaired cellular signaling and the microtubule dynamics underlying granule centralization and release. Several G-protein coupled receptors have been considered targets for influencing platelet activity 43 ; however, more downstream targets are an alternate strategy, especially when their expression is overall restricted to the megakaryocytic lineage. RanBP10 might become one of these targets in the future.…”

The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

“…Hemostasis is a physiological process that stops bleeding upon blood vessel injury. The inappropriate activation of hemostatic mechanisms and unrestrained platelet aggregation may lead to the development of thromboembolic events [1]–[4]. Therefore, it is critical to understand the mechanisms of platelet activation, in order to define novel pharmacological agents to reduce the adverse outcomes of unrestrained platelet activities.…”