P2Y Receptor

P2Y receptors are G protein-coupled receptors (GPCRs) that are activated by adenine and uridine nucleotides and nucleotide sugars. There are eight subtypes of P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), which activate intracellular signaling cascades to regulate a variety of cellular processes, including proliferation, differentiation, phagocytosis, secretion, nociception, cell adhesion, and cell migration. These signaling cascades operate mainly by the sequential activation or deactivation of heterotrimeric and monomeric G proteins, phospholipases, adenylyl and guanylyl cyclases, protein kinases, and phosphodiesterases.

Suramin Sodium
αβ-methylene ATP
MRS 2690
Cangrelor tetrasodium
PSB 1114
NF 340


P2 receptors, as originally classied by Burnstock, respond to extracellular nucleotides. This family of receptors is subdivided into the P2X family of ligand-gated ion channels and the P2Y family of G protein coupled receptors (GPCR).

These two groups were originally defined solely on their distinct pharmacological profiles. The P2X family is potently activated by ATP, α, β-meATP, and β, γ-meATP. The P2Y family is potently activated by 2MeSADP while more modestly by α, β-meATP and β, γ-meATP. Subsequent identification of the signaling properties of P2X receptors and P2Y receptors clearly defined the classification based on being either inotropic receptors or metabotropic receptors.

The P2Y receptor family is a family GPCRs. The P2Y receptors are seven pass transmembrane receptors coupled to heterotrimeric G-proteins. They range in length from 328 to 377 amino acids and have masses of 41 to 53kDa after glycosylation. Transmembrane regions 3, 5, and 7 are essential for nucleotide binding and C-terminal tail allows for coupling to Gα subunits. P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 mainly signal through Gαq, while P2Y12-14, signal through Gαi/o. In addition, P2Y2 and P2Y4 have been shown to couple to Gαi/o and P2Y11 to Gαa. The P2Y2 receptor has been found to directly interact with other signaling molecules. P2Y2 has both an arginine-glycine-aspartic acid (RGD) domain, which interacts with integrins, and a Src-homolgy 3 (SH3) domain, which interacts with Src, and has been shown to associate with the actin-binding protein filamin.

P2Y receptors- functions in the corneal wound response

In one of the first studies performed that shown an increase in ATP released during epithelial wounding, rabbit and rat blood were collected 2-3 seconds after wounding, and then resampled after 3-6 minutes. The researchers discovered that the ATP concentration, using the luciferase assay, increased by two orders of magnitude during that time. The first indication that P2YRs played a role in the cornea began when [Ca2+]i was found to increase when sheets of corneal epithelium were treated with ATP and UTP. BzATP and α, β-MwATP, however, did not increase the Ca2+ response, indicating that P2Y and not P2X receptors were responsible for the activity.

In 2001, Veronica Klepeis wounded a confluent epithelial culture, and she observed that [Ca2+]i increased in cells at the wound edge. However, the Ca2+ was mobilized in the fashion of a “wave,” emanating from the wound edge, and passing to cells further afield from the disrupted cells. Further, it was observed that the wave would pass across acellular regions. From this it was hypothesized that small, diffusible compounds, possibly nucleotides, were being released from the damaged cells. Wound media was then collected from injured cultures, and when non-injured cultures were exposed to the media, there was an [Ca2+]i increase. The intracellular [Ca2+] release could be ablated if the wound media was pretreated with apyrase, an ectonucleotidase, or if the cells were wounded in the presence of apyrase, further indicating the role of nucleotides in the response. When the wound media was sampled, ATP was found to be at a concentration 3.5 times greater than control; however EGF was not found to have increased, removing it from the list od possible agonists responsible for the response.


Oswald, D. J. (2010). The corneal wound response involves reciprocated action by nucleotides released from the epithelium and by glutamate from trigeminal afferent neurons (Doctoral dissertation, Boston University).