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Structure, Pharmacology and Roles in Physiology of the P2Y12 Receptor

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  • First Online:
Protein Reviews

Part of the book series: Advances in Experimental Medicine and Biology ((PROTRE,volume 1051))

Abstract

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. The platelet ADP-receptor which has been denominated P2Y12 receptor is an important target in pharmacotherapy. The receptor couples to Gαi2 mediating an inhibition of cyclic AMP accumulation and additional downstream events including the activation of phosphatidylinositol-3-kinase and Rap1b proteins. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel block P2Y12 receptors and, thereby, inhibit ADP-induced platelet aggregation. These drugs are used for the prevention and therapy of cardiovascular events such as acute coronary syndromes or stroke. The recently published three-dimensional crystal structures of the human P2Y12 receptor in complex with agonists and antagonists will facilitate the development of novel therapeutic agents with reduced adverse effects. P2Y12 receptors are also expressed on vascular smooth muscle cells and may be involved in the pathophysiology of atherogenesis. P2Y12 receptors on microglial cells operate as sensors for adenine nucleotides released during brain injury. A recent study indicated the involvement of microglial P2Y12 receptors in the activity-dependent neuronal plasticity. Interestingly, there is evidence for changes in P2Y12 receptor expression in CNS pathologies including Alzheimer’s diseases and multiple sclerosis. P2Y12 receptors may also be involved in systemic immune modulating responses and the susceptibility to develop bronchial asthma.

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Abbreviations

ADPßS:

adenosine 5-O-2-thiodiphosphate

Akt:

proteinkinase B

AR-C66096:

2-(propylthio)adenosine-5′-O-(β,γ-difluoromethylene)triphosphate

AR-C67085:

2-propylthio-β,γ-dichloromethylene-D-ATP

AR-C69931MX:

N6-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-β,γ-dichloromethylene-ATP)

AZD1283:

ethyl 6-(4-[(benzylsulfonyl) carbamoyl]piperidin-1-yl)-5-cyano-2-methylnicotinate)

AZD6140:

ticagrelor

EL:

extracellular loops

FITC:

fluorescein isothiocyanate

GPCRs:

G-protein-coupled receptors

LPS:

lipopolysaccharide

PDZ:

postsynaptic density 95/disc large/zonula occludens-1–binding domain

PSB-0739:

1-Amino-9,10-dihydro-9,10-dioxo-4-[[4-(phenylamino)-3-sulfophenyl]amino]-2-anthracenesulfonic acid

RASA3:

Ras GTPase-activating protein 3

TM:

transmembrane regions

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  1. Department of Pharmacology and Toxicology, Pharma Center, University of Bonn, D-53127, Bonn, Germany

    Ivar von Kügelgen

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    M. Zouhair Atassi

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von Kügelgen, I. (2017). Structure, Pharmacology and Roles in Physiology of the P2Y12 Receptor. In: Atassi, M. (eds) Protein Reviews. Advances in Experimental Medicine and Biology(), vol 1051. Springer, Singapore. https://doi.org/10.1007/5584_2017_98

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