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Biased Signalling in Platelet G-Protein‐Coupled Receptors

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Biased Signalling in Platelet G-Protein‐Coupled Receptors Canadian Journal of Physiology and Pharmacology Biased signalling in platelet G-protein‐coupled receptors. Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2020-0149.R2 Manuscript Type: Review Date Submitted by the 03-Aug-2020 Author: Complete List of Authors: Thibeault, Pierre; University of Western Ontario Schulich School of Medicine and Dentistry, Physiology and Pharmacology Ramachrandran, Rithwik; University of Western Ontario Schulich School of Medicine and Dentistry, Physiology and Pharmacology Is the invited manuscript for consideration in a Special Not applicableDraft (regular submission) Issue: Keyword: Platelet, GPCR, ADP, Thrombin, Prostanoid https://mc06.manuscriptcentral.com/cjpp-pubs Page 1 of 56 Canadian Journal of Physiology and Pharmacology Biased signalling in platelet G protein‐coupled receptors. Pierre E. Thibeault and Rithwik Ramachandran1 Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street, London, ON, N6A5C1, Canada. 1To whom correspondence should be addressed: Rithwik Ramachandran, [email protected], Department of Physiology and Pharmacology, University of Western Ontario. London, ON, N6A 5C1. Tel: 519-661-2142 Draft 1 https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 2 of 56 Abstract Platelets are small megakaryocyte-derived, anucleate, disk-like structures that play an outsized role in human health and disease. Both a decrease in the number of platelets, as well as a variety of platelet function disorders, result in petechiae or bleeding which can be life threatening. Conversely, the inappropriate activation of platelets, within diseased blood vessels, remains the leading cause of death and morbidity through affecting heart attacks and stroke. The fine balance of the platelet state in healthy individuals is controlled by a number of receptor-mediated signalling pathways that allow the platelet to rapidly respond and maintain haemostasis. G-protein-coupled receptors (GPCRs) are particularly important regulators of platelet function. Here we focus on the major platelet-expressed GPCRs and discuss the roles of downstream signalling pathways (e.g. different G-protein subtypes or -arrestin) in regulating the different phases of the platelet activation. Further, we consider the potential for selectively targeting signalling pathways that may contribute to platelet responses in disease through development of biased agonists. Such selective targeting of GPCR-mediated signalling Draftpathways by drugs, often referred to as biased signalling, holds promise in delivering therapeutic interventions that do not present significant side-effects, especially in finely balanced physiological systems, such as platelet activation in haemostasis. Keyword: Platelet , GPCR , ADP , Thrombin , Prostanoid 2 https://mc06.manuscriptcentral.com/cjpp-pubs Page 3 of 56 Canadian Journal of Physiology and Pharmacology Platelet biogenesis and elimination Platelets were first described in the scientific literature in the mid to late 1800’s by a number of scientists, including William Osler and George Hayem, who recognized them as small anucleate disk-like structures in blood (Cooper, 2005). At this time, platelets were believed to be fragments of disintegrated leukocytes, clots of fibrin, or precursors to red blood cells. Giulio Bizzozero is widely credited with identifying platelets as a distinct morphological element in blood and for conducting the definitive studies that uncovered the critical role of platelets in haemostasis (Ribatti & Crivellato, 2007). Bizzozero, also credited with first describing bone marrow megakaryocytes, however failed to recognize them as the source of platelets, a finding attributed to James Wright who noted similarities between granule contents in megakaryocytes and platelets (Kaushansky, 2008). The production of platelets (thrombopoiesis) occurs primarily in the bone marrow from megakaryocytes. Megakaryocytes, formed by the differentiation of hematopoietic stem cells, home to the perivascular niche where they interact with sinusoidal bone marrow endothelial cells and form dynamic transendothelialDraft pseudopods which project into the lumen of bone marrow sinusoids. These extensions into the sinusoids elongate and are described as pro- platelets, which remain tethered to the megakaryocytes by thin cytoplasmic bridges. The release of the platelet into the blood occurs from the tip of the pro-platelets and represents the final step in the process of platelet biogenesis (Machlus & Italiano, 2013; Noetzli Leila J. et al., 2019). Platelets have a short lifespan and are eliminated within days (4-6 days in mice; 5-10 days in humans) (Leeksma & Cohen, 1955; Robinson et al., 2000) via seclusion in the spleen and other organs, or through deposition at sites of vascular injury. Even in the absence of such consumption, aged-platelets undergo apoptosis and are removed from circulation. A shift in the balance of the pro-apoptotic (BAX-BAK) and anti-apoptotic (BCL2) proteins is believed to play an important role in this spontaneous apoptosis of ageing platelets (Mason et al., 2007). Thus, constant production and elimination of platelets serves to maintain normal platelet count in a healthy individual at around 150,000-300,000 cells per microliter. The delicate balance of platelets in haemostasis and thrombosis Throughout their short lifespan, platelets must perform a delicate balancing act. They must remain poised for activation in response to a disruption of vascular integrity yet remain in their inactive state within intact vessels. Platelets are aided in performing this delicate act by the 3 https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 4 of 56 endothelial cells lining the blood vessels. The intact endothelial monolayer lining the inner surface of blood vessels acts to actively suppress platelet activation. Healthy vascular endothelia do so by physically separating platelets from the underlying platelet-activating matrix components, such as collagen, and by constantly producing and secreting factors that prevent platelet activation (e.g. thrombomodulin, ectonucleotides, prostaglandin I2 (PGI2), nitric oxide (NO)). In the event of vascular injury, platelet activation is rapid and is initially mediated by platelet glycoprotein (GP) Ib-V-IX interaction with von Willebrand factor (vWF) in the subendothelial matrix. This initial interaction slows the circulating platelets and enables further interaction between platelet adhesion receptors/integrins and their counter receptors; and/or adhesive matrix components (e.g. GPVI-Collagen or IIb3-Fibronectin). At the cellular level, these signals also trigger a cytoskeletal rearrangement in the platelets and cause platelet spreading which increases their attachment to subendothelial surfaces at the sites of injury. The initial activation of platelets further involves signalling mediated by factors released from the damaged cells in an injured blood vessel (e.g. ADP)Draft and produced during coagulation (e.g. thrombin). The inflammatory response accompanying the injury may also produce factors (e.g. platelet-activating factor) that further activate platelets. Crucially, these signals from the injured vascular cells are amplified dramatically by the release of platelet granule contents including thromboxane A2 (TXA2), Adenosine diphosphate (ADP), and serotonin, which further amplify platelet activation and serve to recruit additional platelets to the site of a growing thrombus. The release of platelet granules involves cytoskeletal rearrangement, fusion of granules with the open-canalicular system, and release of granule contents (Flaumenhaft Robert, 2003; Selvadurai & Hamilton, 2018). Activated platelets also provide a surface on which additional thrombin is generated and fibrin can accumulate (Andersen et al., 1999). Many of the factors that contribute to platelet activation in response to injury are also engaged in the inappropriate activation of platelets, which occurs within blood vessels in disease. Endothelial dysfunction, resulting from diseases such as diabetes, leads to a loss of negative endothelial derived signals (PGI2 and NO) and is an important driver of platelet activation in disease (Deanfield et al., 2005; H. Ding & Triggle, 2010; Pober et al., 2009). Factors that are produced in vessel injury can also be generated in unhealthy blood vessels, as a result of inappropriate endothelial signalling. For example, lysophosphatidic acid (LPA), in atherosclerotic 4 https://mc06.manuscriptcentral.com/cjpp-pubs Page 5 of 56 Canadian Journal of Physiology and Pharmacology plaques, can trigger platelet activation that in turn causes the release of factors such as ADP and TXA2 from platelets, which trigger inappropriate platelet aggregation and thrombosis. Many of these important mediators of platelet activation act on platelet cell surface G- protein coupled receptors (GPCRs) to mediate the various phases of platelet activation. In the following sections, we discuss the major receptor proximal signaling pathways engaged by GPCRs, provide a brief overview of the different GPCRs expressed in human platelets, and discuss whether selective targeting of signalling pathways downstream of these different platelet GPCRs might provide a route to safer and more efficacious anti-platelet agents. GPCR signalling mechanisms GPCRs form a large family of cell surface receptors that respond to a diversity of activators
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