Membrane-bound P2-receptors mediate the actions of extracellular
nucleotides in cell-to-cell signalling. P2X-receptors are
ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of
G-protein-coupled receptors (GPCRs). So far, the P2Y family is composed out of 8 human subtypes that have been cloned and functionally defined; species orthologues have been found in many vertebrates. P2Y1-, P2Y2-, P2Y4-, P2Y6-, and P2Y11-receptors all couple to stimulation of
phospholipase C. The P2Y11-receptor mediates in addition a stimulation of
adenylate cyclase. In contrast, activation of the P2Y12-, P2Y13-, and P2Y14-receptors causes an inhibition of
adenylate cyclase activity. The expression of P2Y1-receptors is widespread. The receptor is involved in blood platelet aggregation, vasodilatation and neuromodulation. It is activated by
ADP and
ADP analogues including
2-methylthio-ADP (2-MeSADP). 2'-Deoxy-N6-methyladenosine-3',5'-bisphosphate (
MRS2179) and 2-chloro-N6-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate (
MRS2279) are potent and selective antagonists. P2Y2 transcripts are abundantly distributed. One important example for its functional role is the control of
chloride ion fluxes in airway epithelia. The P2Y2-receptor is activated by
UTP and
ATP and blocked by
suramin. The P2Y2-agonist
diquafosol is used for the treatment of the
dry eye disease. P2Y4-receptors are expressed in the placenta and in epithelia. The human P2Y4-receptor has a strong preference for
UTP as agonist, whereas the rat P2Y4-receptor is activated about equally by
UTP and
ATP. The P2Y4-receptor is not blocked by
suramin. The P2Y6-receptor has a widespread distribution including heart, blood vessels, and brain. The receptor prefers
UDP as agonist and is selectively blocked by 1,2-di-(4-isothiocyanatophenyl)ethane (MRS2567). The P2Y11-receptor may play a role in the differentiation of immunocytes. The human P2Y11-receptor is activated by
ATP as naturally occurring agonist and it is blocked by
suramin and
reactive blue 2 (RB2). The P2Y12-receptor plays a crucial role in platelet aggregation as well as in inhibition of neuronal cells. It is activated by
ADP and very potently by
2-methylthio-ADP.
Nucleotide antagonists including N6-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (=
cangrelor;
AR-C69931MX), the
nucleoside analogue
AZD6140, as well as active metabolites of the
thienopyridine compounds
clopidogrel and
prasugrel block the receptor. These P2Y12-antagonists are used in
pharmacotherapy to inhibit platelet aggregation. The P2Y13-receptor is expressed in immunocytes and neuronal cells and is again activated by
ADP and
2-methylthio-ADP. The 2-chloro-5-nitro
pyridoxal-phosphate analogue 6-(2'-chloro-5'-nitro-azophenyl)-pyridoxal-alpha5-phosphate (
MRS2211) is a selective antagonist.
mRNA encoding for the human P2Y14-receptor is found in many tissues. However, a physiological role of the receptor has not yet been established.
UDP-glucose and related analogues act as agonists; antagonists are not known. Finally,
UDP has been reported to act on receptors for cysteinyl
leukotrienes as an additional agonist--indicating a dual agonist specificity of these receptors.