Rare platelet G protein-coupled receptor variants: what can we learn?

S P Nisar, M L Jones, M R Cunningham, A D Mumford, S J Mundell, UK GAPP Study Group

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Platelet expressed G protein-coupled receptors (GPCRs) are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti-thrombotic drug therapy is associated with high inter-patient variability in therapeutic response and adverse bleeding side-effects. In order to optimise the use of existing antiplatelet drugs and to develop new therapies more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review we describe how an integrated functional genomics strategy has contributed important structure-function information about platelet GPCRs with specific emphasis upon purinergic (P2Y12 ) and thromboxane (TP-α) receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders.

LanguageEnglish
JournalBritish Journal of Pharmacology
Early online date24 Nov 2014
DOIs
Publication statusPublished - 2015

Fingerprint

G-Protein-Coupled Receptors
Blood Platelets
Hemorrhage
Thromboxane Receptors
Drug Therapy
Thromboxanes
Platelet Aggregation Inhibitors
Therapeutics
Genomics
Coronary Artery Disease
Thrombosis
Stroke
Pharmacology
Mutation
Proteins

Keywords

  • platelet function
  • antiplatelet drugs
  • G protein-coupled receptors

Cite this

Nisar, S P ; Jones, M L ; Cunningham, M R ; Mumford, A D ; Mundell, S J ; UK GAPP Study Group. / Rare platelet G protein-coupled receptor variants : what can we learn?. In: British Journal of Pharmacology. 2015.
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Rare platelet G protein-coupled receptor variants : what can we learn? / Nisar, S P; Jones, M L; Cunningham, M R; Mumford, A D; Mundell, S J; UK GAPP Study Group.

In: British Journal of Pharmacology, 2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare platelet G protein-coupled receptor variants

T2 - British Journal of Pharmacology

AU - Nisar, S P

AU - Jones, M L

AU - Cunningham, M R

AU - Mumford, A D

AU - Mundell, S J

AU - UK GAPP Study Group

N1 - This article is protected by copyright. All rights reserved.

PY - 2015

Y1 - 2015

N2 - Platelet expressed G protein-coupled receptors (GPCRs) are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti-thrombotic drug therapy is associated with high inter-patient variability in therapeutic response and adverse bleeding side-effects. In order to optimise the use of existing antiplatelet drugs and to develop new therapies more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review we describe how an integrated functional genomics strategy has contributed important structure-function information about platelet GPCRs with specific emphasis upon purinergic (P2Y12 ) and thromboxane (TP-α) receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders.

AB - Platelet expressed G protein-coupled receptors (GPCRs) are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti-thrombotic drug therapy is associated with high inter-patient variability in therapeutic response and adverse bleeding side-effects. In order to optimise the use of existing antiplatelet drugs and to develop new therapies more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review we describe how an integrated functional genomics strategy has contributed important structure-function information about platelet GPCRs with specific emphasis upon purinergic (P2Y12 ) and thromboxane (TP-α) receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders.

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KW - antiplatelet drugs

KW - G protein-coupled receptors

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