P2Y receptors are a family of

purinergic Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, ...

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

s, stimulated by

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

s such as

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...

uridine triphosphate Uridine-5′-triphosphate (UTP) is a pyrimidine nucleoside triphosphate, consisting of the organic base uracil linked to the 1′ carbon of the ribose sugar, and esterified with tri-phosphoric acid at the 5′ position. Its main role is as substra ...

uridine diphosphate Uridine diphosphate, abbreviated UDP, is an organic compound. It is an ester of pyrophosphoric acid with the nucleoside uridine. UDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase uracil. UDP is an important fa ...

and UDP-glucose.To date, 8 P2Y receptors have been cloned in humans: P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₂, P2Y₁₃ and P2Y₁₄. P2Y receptors are present in almost all human tissues where they exert various biological functions based on their G-protein coupling. P2Y receptors mediate responses including vasodilation, blood clotting, and immune response. Due to their ubiquity and variety in function, they are a common

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

in pharmacological development.

Structure

P2Y receptors are membrane proteins belonging to the class A family of G protein-coupled receptors (GPCRs). P2Y receptor proteins display large-scale structural domains typical of GPCRs, consisting of seven hydrophobic transmembrane helices connected by three short extracellular loops and three variably sized intracellular loops; an extracellular

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

; and an intracellular

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

. The extracellular regions interact with the receptor ligands, while the intracellular regions activate the G protein, control receptor internalization, and mediate dimerization. Similar to other GPCRs, P2Y receptors can form both homodimers and

heterodimers In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

. These dimeric forms may vary significantly in their biochemical and pharmacological properties from the monomeric receptor. 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

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues which can form two disulfide bridges, one between the N-terminus domain and the proximal extracellular loop and another between the two remaining extracellular loops. These disulfide bonds have been shown to be involved in ligand binding and signal transduction. In addition, several polar residues found within the transmembrane helices are highly conserved across both species and receptor subtypes. Mutational analysis has suggested that these residues are integral to the ligand-binding mechanism of P2Y receptors. Outside of these conserved regions, the P2Y receptor family exhibits unusually high diversity in

primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

, with P2Y₁ sharing only 19% of its primary structure with P2Y₁₂. Despite this, the individual P2Y subtypes are highly conserved across species, with human and mouse P2Y receptors sharing 95% of amino acids. The ligand-binding mechanisms of P2Y receptors are not currently well established. 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. Recent

x-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

of the human P2Y₁₂ receptor has shown several structural irregularities in regions that are typically highly conserved across GPCRs. 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.

Signal transduction

P2Y receptors respond either positively or negatively to the presence of nucleotides in extracellular solution. Nucleotides may be divided into two categories:

purine Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted puri ...

s and

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...

s. 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. 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. Voltage-independent Ca²⁺ channels allow for the free flow of Ca²⁺ ions from the cell activated by P2Y receptors. 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. Changes in the concentration of Ca²⁺ have many important ramifications for the cell, including regulation of cell metabolism (e.g.

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. 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.

Pharmacology

Many commonly prescribed medications target P2Y receptors, and active research is being conducted into developing new drugs targeting these receptors. The most commonly prescribed drug targeting P2Y receptors is

clopidogrel Clopidogrel, sold under the brand name Plavix among others, is an antiplatelet drug, antiplatelet medication used to reduce the risk of Cardiovascular disease, heart disease and stroke in those at high risk. It is also used together with aspi ...

, an antiplatelet medication which acts on the P2Y₁₂ receptor in a manner shared with other

thienopyridine Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity. They have a significant role in the management of cardiovascular disease. Clinical Uses They are used in the managem ...

s. Other pharmaceutical applications include denufosol, which targets P2Y₂ and is being investigated for the treatment of

cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

, and diquafosol, a P2Y₂

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

used in the treatment of dry eye disease. P2Y₆ receptors have been shown to play a role in cerebral

vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...

. UDP-analogs which bind to this receptor have been investigated as possible treatments for

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

s. 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 A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

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

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

, and cardio-protection.

Coupling

The biological effects of P2Y receptor activation depends on how they couple to downstream signalling pathways, either via G_i, G_q/11 or G_s G proteins. Human P2Y receptors have the following G protein coupling: The gaps in P2Y receptor numbering is due to that several receptors (P2Y₃, P2Y₅, P2Y₇, P2Y₈, P2Y₉, P2Y₁₀) were thought to be P2Y receptors when they were cloned, when in fact they are not.

References

External links

Ivar von Kügelgen: Pharmacology of mammalian P2X- and P2Y-receptors, BIOTREND Reviews No. 03, September 2008,© 2008 BIOTREND Chemicals AG
* * {{G protein-coupled receptors G protein-coupled receptors