P2Y receptor

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Simplified illustration of extracellular purinergic signalling
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P2Y receptors are a family of

P2Y receptors are

In addition to the structural domains typical of all GPCRs, some structural elements are common across P2Y receptor subtypes. All P2Y receptors contain four extracellular

The ligand-binding mechanisms of P2Y receptors are not currently well established.[8] The binding complex of P2Y receptors with ATP is of significant interest, as no P2Y receptor contains amino acids sequences similar to any of the many established ATP-binding sites.^[7] Recent x-ray crystallography of the human P2Y₁₂ receptor has shown several structural irregularities in regions that are typically highly conserved across GPCRs.^[8]

In contrast to the unusual structure and behavior of the extracellular ligand binding domains, P2Y intracellular domains appear to be structurally and mechanistically similar to other GPCRs.^[6]

Signal transduction

P2Y receptors respond either positively or negatively to the presence of nucleotides in extracellular solution.^[9] Nucleotides may be divided into two categories: purines and pyrimidines. Individual P2Y receptor species may respond to only purines, only pyrimidines, or both; the activation profiles of the eight known P2Y receptors are listed below.^[9]

The activity of P2Y receptors is linked to a signal cascade originating in regulation of the flow of Ca²⁺ and K⁺ ions by the receptor's interactions with G proteins, modulating access to Ca²⁺ and K⁺ channels, though the exact behavior is dependent upon individual receptor species.^[10] Voltage-independent Ca²⁺ channels allow for the free flow of Ca²⁺ ions from the cell activated by P2Y receptors.^[10] Oscillation of Ca²⁺ concentration is directly affected by the signal-transduction activity of P2Y₁; specifically, through protein kinase C phosphorylation of Thr339 in the carboxy terminus of the P2Y₁ receptor.^[10]

Changes in the concentration of Ca²⁺ have many important ramifications for the cell, including regulation of cell metabolism (e.g. autophagy initiation / regulation), ATP production (through Ca²⁺ entering the mitochondrial outer mitochondrial membrane and stimulation of mitochondrial dehydrogenases leading to the production of ATP), and the possibility of triggering apoptosis.^[11][12] Both autophagy and apoptosis are cell stress responses that play significant roles in cells' overall life cycles, though autophagy seeks to preserve the viability of the cell by recycling unit parts of organelles, while apoptosis acts in the interest of the whole organism at the expense of the cell undergoing apoptosis.^[12]

Pharmacology

Many commonly prescribed medications target P2Y receptors, and active research is being conducted into developing new drugs targeting these receptors.^[3] The most commonly prescribed drug targeting P2Y receptors is clopidogrel, an antiplatelet medication which acts on the P2Y₁₂ receptor in a manner shared with other thienopyridines.^[14] Other pharmaceutical applications include denufosol, which targets P2Y₂ and is being investigated for the treatment of cystic fibrosis, and diquafosol, a P2Y₂ agonist used in the treatment of dry eye disease.^[15][16][17]

P2Y₆ receptors have been shown to play a role in cerebral vasodilation. UDP-analogs which bind to this receptor have been investigated as possible treatments for migraines.^[18][17]

P2Y₁₁ is a regulator of immune response, and a common polymorphism carried by almost 20% of North European caucasians give increased risk of myocardial infarction, making P2Y₁₁ an interesting drug target candidate for treatment of myocardial infarction.^[4][16][17]

In addition to established uses, pharmaceutical research has been conducted into the role of P2Y receptors in

• Receptor (biochemistry)
• Purinergic signalling
• Membrane protein
• Receptor theory

References