* 600041

PURINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 2; P2RY2


Alternative titles; symbols

PURINOCEPTOR P2Y2; P2Y2; P2Y2R
P2U NUCLEOTIDE RECEPTOR; P2UR


HGNC Approved Gene Symbol: P2RY2

Cytogenetic location: 11q13.4     Genomic coordinates (GRCh38): 11:73,218,281-73,242,427 (from NCBI)


TEXT

Cloning and Expression

Parr et al. (1994) reported the sequence and functional expression of a cDNA cloned from human airway epithelial cells that encodes P2RY2, a protein with properties of a P2U nucleotide receptor. They also isolated an identical cDNA from human colonic epithelial cells, indicating that this is the same P2U receptor that had been functionally identified in other human tissues.


Gene Function

The chloride ion secretory pathway that is defective in cystic fibrosis (219700) can be bypassed by an alternative pathway for chloride ion transport that is activated by extracellular nucleotides. Accordingly, the P2 receptor that mediates this effect is a therapeutic target for improving chloride secretion in CF patients. Using a retrovirus system, Parr et al. (1994) stably expressed a human airway P2RY2 clone in 1321N1 astrocytoma cells, a human cell line unresponsive to extracellular nucleotides. Studies of inositol phosphate accumulation and intracellular Ca(2+) mobilization induced by extracellular nucleotides in 1321N1 cells expressing the receptor identified this clone as the target receptor in human airway epithelia. Expression of P2RY2 in 1321N1 cells revealed evidence for autocrine ATP release and stimulation of transduced receptors. Thus, P2RY2 expression in the cell line was proposed as a useful system for studying autocrine regulatory mechanisms and for screening potential therapeutic drugs.

Katzur et al. (1999) reported that in single endometrial carcinoma HEC-1A and Ishikawa cells, ATP induced a rapid and extracellular Ca(2+)-independent rise in cytosolic Ca(2+) concentration in a dose-dependent manner, with an ED50 of about 10 microg. This ligand-selective profile indicated the expression of the P2RY2 subtype in endometrial cells. Accordingly, RT-PCR using P2RY2 primers amplified the expected transcript from both cell lines. The coupling of these receptors to phospholipase C was confirmed. The authors concluded that P2RY2 may participate in control of the cell cycle of endometrial carcinoma cells.

Tai et al. (2000) studied the expression and regulation of the P2UR gene in human granulosa-luteal cells (GLCs) by RT-PCR and Northern blot analysis. Expression of P2UR mRNA was downregulated by human chorionic gonadotropin (CG) in a dose- and time-dependent manner. Treatment with 8-bromo-cAMP and forskolin also attenuated P2UR mRNA levels. The authors concluded that the P2UR mRNA is expressed in human GLCs and that P2UR mRNA is regulated by human CG, cAMP, and forskolin. These findings further supported a potential role of this neurotransmitter receptor in the human ovary.

Adrian et al. (2000) analyzed the expression of several purinergic receptors during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. Basal expression of P2Y2 was relatively high in undifferentiated cells, and expression declined during granulocytic differentiation. P2Y2 expression also decreased during monocytic differentiation and was nearly undetectable after 48 hours.

Arthur et al. (2005) found that activation of P2ry2 by ATP-gamma-S, a nonhydrolyzable ATP analog, in the presence of NGF (162030) led to colocalization and association of Trka (NTRK1; 191315) and P2ry2 and was required for enhanced neuronal differentiation in a rat neuronal precursor cell line. Depletion of P2ry2 by genetic means or by small interfering RNA abolished the ATP-gamma-S-mediated increase in neuronal differentiation. Moreover, in vivo injection of ATP-gamma-S into the sciatic nerve of wildtype mice, but not P2ry2-null mice, increased expression of Gap43 (162060), a marker for axonal growth. Arthur et al. (2005) concluded that P2RY2 is a morphogen receptor that potentiates neurotrophin signaling in neuronal development and regeneration.

Chen et al. (2006) found that human neutrophils release ATP from the leading edge of the cell surface to amplify chemotactic signals and direct cell orientation by feedback through the P2Y2 nucleotide receptors. Neutrophils rapidly hydrolyze released ATP to adenosine that then acts via A3-type adenosine receptors, which are recruited to the leading edge to promote cell migration. Thus, Chen et al. (2006) found that ATP release and autocrine feedback through P2Y2 and A3 receptors provide signal amplification, controlling gradient sensing and migration of neutrophils.

Through several lines of evidence, Elliott et al. (2009) identified extracellular nucleotides as a critical apoptotic cell 'find-me' signal. Elliott et al. (2009) demonstrated the caspase (see 147678)-dependent release of ATP and UTP in equimolar quantities during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to that of apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or the expression of ectopic CD39, 601752) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. Elliott et al. (2009) then identified the ATP/UTP receptor P2Y2 as a critical sensor of nucleotides released by apoptotic cells using RNA interference-mediated depletion studies in monocytes, and macrophages from P2Y2-null mice. The relevance of nucleotides in apoptotic cell clearance in vivo was revealed by 2 approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a 3-fold greater recruitment of monocytes and macrophages than supernatants from healthy cells did; this recruitment was abolished by depletion of nucleotides and was significantly decreased in P2Y2-null mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacologic inhibition or in P2Y2-null mice). Elliott et al. (2009) concluded that their results identified nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y2-dependent recruitment of phagocytes, and provided evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo.


Mapping

Using PCR analysis of human-rodent hybrid cell line DNAs, Dasari et al. (1996) mapped the human P2RY2 gene to chromosome 11q13.5-q14.1. The authors noted that several G protein-coupled receptor genes, namely the beta adrenergic receptor, the angiotensin receptor-like-1, and the muscarinic cholinergic receptor-1, have been localized to the same region of chromosome 11. By sequence tagged site (STS) mapping using the National Center for Biotechnology Information (NCBI) database, Somers et al. (1997) demonstrated that the P2RY2 gene maps within less than 4 cM of the P2RY6 gene (602451), which they had mapped to 11q13.5 by fluorescence in situ hybridization and STS mapping. This was the first chromosomal clustering of this gene family to be described.


REFERENCES

  1. Adrian, K., Bernhard, M. K., Breitinger, H.-G., Ogilvie, A. Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochim. Biophys. Acta 1492: 127-138, 2000. [PubMed: 11004484, related citations] [Full Text]

  2. Arthur, D. B., Akassoglou, K., Insel, P. A. P2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation. Proc. Nat. Acad. Sci. 102: 19138-19143, 2005. [PubMed: 16365320, images, related citations] [Full Text]

  3. Chen, Y., Corriden, R., Inoue, Y., Yip, L., Hashiguchi, N., Zinkernagel, A., Nizet, V., Insel, P. A., Junger, W. G. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314: 1792-1795, 2006. [PubMed: 17170310, related citations] [Full Text]

  4. Dasari, V. R., Sandhu, A. K., Mills, D. C. B., Athwal, R. S., Kunapuli, S. P. Mapping of the P2U purinergic receptor gene to human chromosome 11q13.5-14.1. Somat. Cell Molec. Genet. 22: 75-79, 1996. [PubMed: 8643996, related citations] [Full Text]

  5. Elliott, M. R., Chekeni, F. B., Trampont, P. C., Lazarowski, E. R., Kadl, A., Walk, S. F., Park, D., Woodson, R. I., Ostankovich, M., Sharma, P., Lysiak, J. J., Harden, T. K., Leitinger, N., Ravichandran, K. S. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461: 282-286, 2009. [PubMed: 19741708, images, related citations] [Full Text]

  6. Katzur, A. C., Koshimizu, T.-A., Tomic, M., Schultze-Mosgau, A., Ortmann, O., Stojilkovic, S. S. Expression and responsiveness of P2Y2 receptors in human endometrial cancer cell lines. J. Clin. Endocr. Metab. 84: 4085-4091, 1999. [PubMed: 10566654, related citations] [Full Text]

  7. Parr, C. E., Sullivan, D. M., Paradiso, A. M., Lazarowski, E. R., Burch, L. H., Olsen, J. C., Erb, L., Weisman, G. A., Boucher, R. C., Turner, J. T. Cloning and expression of a human P(2U) nucleotide receptor, a target for cystic fibrosis pharmacotherapy. Proc. Nat. Acad. Sci. 91: 3275-3279, 1994. Note: Erratum: Proc. Nat. Acad. Sci. 91: 13067 only, 1994. [PubMed: 8159738, related citations] [Full Text]

  8. Somers, G. R., Hammet, F., Woollatt, E., Richards, R. I., Southey, M. C., Venter, D. J. Chromosomal localization of the human P2Y(6) purinoceptor gene and phylogenetic analysis of the P2y purinoceptor family. Genomics 44: 127-130, 1997. [PubMed: 9286708, related citations] [Full Text]

  9. Tai, C.-J., Kang, S. K., Cheng, K. W., Choi, K.-C., Nathwani, P. S., Leung, P. C. K. Expression and regulation of P2U-purinergic receptor in human granulosa-luteal cells. J. Clin. Endocr. Metab. 85: 1591-1597, 2000. [PubMed: 10770202, related citations] [Full Text]


Ada Hamosh - updated : 10/13/2009
Ada Hamosh - updated : 1/23/2007
Patricia A. Hartz - updated : 1/30/2006
Patricia A. Hartz - updated : 3/7/2005
John A. Phillips, III - updated : 11/13/2000
John A. Phillips, III - updated : 10/2/2000
Jennifer P. Macke - updated : 10/30/1996
Creation Date:
Victor A. McKusick : 7/18/1994
alopez : 05/21/2019
alopez : 10/17/2016
terry : 08/03/2012
alopez : 10/22/2009
terry : 10/13/2009
alopez : 1/25/2007
terry : 1/23/2007
mgross : 1/30/2006
mgross : 3/7/2005
mgross : 12/7/2000
terry : 11/13/2000
mgross : 10/3/2000
terry : 10/2/2000
mgross : 4/8/1999
alopez : 3/18/1998
terry : 9/30/1997
jamie : 11/15/1996
jamie : 11/6/1996
jamie : 10/30/1996
jamie : 10/30/1996
mark : 3/31/1996
mark : 12/4/1995
mimadm : 7/30/1994
jason : 7/18/1994

* 600041

PURINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 2; P2RY2


Alternative titles; symbols

PURINOCEPTOR P2Y2; P2Y2; P2Y2R
P2U NUCLEOTIDE RECEPTOR; P2UR


HGNC Approved Gene Symbol: P2RY2

Cytogenetic location: 11q13.4     Genomic coordinates (GRCh38): 11:73,218,281-73,242,427 (from NCBI)


TEXT

Cloning and Expression

Parr et al. (1994) reported the sequence and functional expression of a cDNA cloned from human airway epithelial cells that encodes P2RY2, a protein with properties of a P2U nucleotide receptor. They also isolated an identical cDNA from human colonic epithelial cells, indicating that this is the same P2U receptor that had been functionally identified in other human tissues.


Gene Function

The chloride ion secretory pathway that is defective in cystic fibrosis (219700) can be bypassed by an alternative pathway for chloride ion transport that is activated by extracellular nucleotides. Accordingly, the P2 receptor that mediates this effect is a therapeutic target for improving chloride secretion in CF patients. Using a retrovirus system, Parr et al. (1994) stably expressed a human airway P2RY2 clone in 1321N1 astrocytoma cells, a human cell line unresponsive to extracellular nucleotides. Studies of inositol phosphate accumulation and intracellular Ca(2+) mobilization induced by extracellular nucleotides in 1321N1 cells expressing the receptor identified this clone as the target receptor in human airway epithelia. Expression of P2RY2 in 1321N1 cells revealed evidence for autocrine ATP release and stimulation of transduced receptors. Thus, P2RY2 expression in the cell line was proposed as a useful system for studying autocrine regulatory mechanisms and for screening potential therapeutic drugs.

Katzur et al. (1999) reported that in single endometrial carcinoma HEC-1A and Ishikawa cells, ATP induced a rapid and extracellular Ca(2+)-independent rise in cytosolic Ca(2+) concentration in a dose-dependent manner, with an ED50 of about 10 microg. This ligand-selective profile indicated the expression of the P2RY2 subtype in endometrial cells. Accordingly, RT-PCR using P2RY2 primers amplified the expected transcript from both cell lines. The coupling of these receptors to phospholipase C was confirmed. The authors concluded that P2RY2 may participate in control of the cell cycle of endometrial carcinoma cells.

Tai et al. (2000) studied the expression and regulation of the P2UR gene in human granulosa-luteal cells (GLCs) by RT-PCR and Northern blot analysis. Expression of P2UR mRNA was downregulated by human chorionic gonadotropin (CG) in a dose- and time-dependent manner. Treatment with 8-bromo-cAMP and forskolin also attenuated P2UR mRNA levels. The authors concluded that the P2UR mRNA is expressed in human GLCs and that P2UR mRNA is regulated by human CG, cAMP, and forskolin. These findings further supported a potential role of this neurotransmitter receptor in the human ovary.

Adrian et al. (2000) analyzed the expression of several purinergic receptors during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. Basal expression of P2Y2 was relatively high in undifferentiated cells, and expression declined during granulocytic differentiation. P2Y2 expression also decreased during monocytic differentiation and was nearly undetectable after 48 hours.

Arthur et al. (2005) found that activation of P2ry2 by ATP-gamma-S, a nonhydrolyzable ATP analog, in the presence of NGF (162030) led to colocalization and association of Trka (NTRK1; 191315) and P2ry2 and was required for enhanced neuronal differentiation in a rat neuronal precursor cell line. Depletion of P2ry2 by genetic means or by small interfering RNA abolished the ATP-gamma-S-mediated increase in neuronal differentiation. Moreover, in vivo injection of ATP-gamma-S into the sciatic nerve of wildtype mice, but not P2ry2-null mice, increased expression of Gap43 (162060), a marker for axonal growth. Arthur et al. (2005) concluded that P2RY2 is a morphogen receptor that potentiates neurotrophin signaling in neuronal development and regeneration.

Chen et al. (2006) found that human neutrophils release ATP from the leading edge of the cell surface to amplify chemotactic signals and direct cell orientation by feedback through the P2Y2 nucleotide receptors. Neutrophils rapidly hydrolyze released ATP to adenosine that then acts via A3-type adenosine receptors, which are recruited to the leading edge to promote cell migration. Thus, Chen et al. (2006) found that ATP release and autocrine feedback through P2Y2 and A3 receptors provide signal amplification, controlling gradient sensing and migration of neutrophils.

Through several lines of evidence, Elliott et al. (2009) identified extracellular nucleotides as a critical apoptotic cell 'find-me' signal. Elliott et al. (2009) demonstrated the caspase (see 147678)-dependent release of ATP and UTP in equimolar quantities during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to that of apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or the expression of ectopic CD39, 601752) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. Elliott et al. (2009) then identified the ATP/UTP receptor P2Y2 as a critical sensor of nucleotides released by apoptotic cells using RNA interference-mediated depletion studies in monocytes, and macrophages from P2Y2-null mice. The relevance of nucleotides in apoptotic cell clearance in vivo was revealed by 2 approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a 3-fold greater recruitment of monocytes and macrophages than supernatants from healthy cells did; this recruitment was abolished by depletion of nucleotides and was significantly decreased in P2Y2-null mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacologic inhibition or in P2Y2-null mice). Elliott et al. (2009) concluded that their results identified nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y2-dependent recruitment of phagocytes, and provided evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo.


Mapping

Using PCR analysis of human-rodent hybrid cell line DNAs, Dasari et al. (1996) mapped the human P2RY2 gene to chromosome 11q13.5-q14.1. The authors noted that several G protein-coupled receptor genes, namely the beta adrenergic receptor, the angiotensin receptor-like-1, and the muscarinic cholinergic receptor-1, have been localized to the same region of chromosome 11. By sequence tagged site (STS) mapping using the National Center for Biotechnology Information (NCBI) database, Somers et al. (1997) demonstrated that the P2RY2 gene maps within less than 4 cM of the P2RY6 gene (602451), which they had mapped to 11q13.5 by fluorescence in situ hybridization and STS mapping. This was the first chromosomal clustering of this gene family to be described.


REFERENCES

  1. Adrian, K., Bernhard, M. K., Breitinger, H.-G., Ogilvie, A. Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochim. Biophys. Acta 1492: 127-138, 2000. [PubMed: 11004484] [Full Text: https://doi.org/10.1016/s0167-4781(00)00094-4]

  2. Arthur, D. B., Akassoglou, K., Insel, P. A. P2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation. Proc. Nat. Acad. Sci. 102: 19138-19143, 2005. [PubMed: 16365320] [Full Text: https://doi.org/10.1073/pnas.0505913102]

  3. Chen, Y., Corriden, R., Inoue, Y., Yip, L., Hashiguchi, N., Zinkernagel, A., Nizet, V., Insel, P. A., Junger, W. G. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314: 1792-1795, 2006. [PubMed: 17170310] [Full Text: https://doi.org/10.1126/science.1132559]

  4. Dasari, V. R., Sandhu, A. K., Mills, D. C. B., Athwal, R. S., Kunapuli, S. P. Mapping of the P2U purinergic receptor gene to human chromosome 11q13.5-14.1. Somat. Cell Molec. Genet. 22: 75-79, 1996. [PubMed: 8643996] [Full Text: https://doi.org/10.1007/BF02374378]

  5. Elliott, M. R., Chekeni, F. B., Trampont, P. C., Lazarowski, E. R., Kadl, A., Walk, S. F., Park, D., Woodson, R. I., Ostankovich, M., Sharma, P., Lysiak, J. J., Harden, T. K., Leitinger, N., Ravichandran, K. S. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461: 282-286, 2009. [PubMed: 19741708] [Full Text: https://doi.org/10.1038/nature08296]

  6. Katzur, A. C., Koshimizu, T.-A., Tomic, M., Schultze-Mosgau, A., Ortmann, O., Stojilkovic, S. S. Expression and responsiveness of P2Y2 receptors in human endometrial cancer cell lines. J. Clin. Endocr. Metab. 84: 4085-4091, 1999. [PubMed: 10566654] [Full Text: https://doi.org/10.1210/jcem.84.11.6119]

  7. Parr, C. E., Sullivan, D. M., Paradiso, A. M., Lazarowski, E. R., Burch, L. H., Olsen, J. C., Erb, L., Weisman, G. A., Boucher, R. C., Turner, J. T. Cloning and expression of a human P(2U) nucleotide receptor, a target for cystic fibrosis pharmacotherapy. Proc. Nat. Acad. Sci. 91: 3275-3279, 1994. Note: Erratum: Proc. Nat. Acad. Sci. 91: 13067 only, 1994. [PubMed: 8159738] [Full Text: https://doi.org/10.1073/pnas.91.8.3275]

  8. Somers, G. R., Hammet, F., Woollatt, E., Richards, R. I., Southey, M. C., Venter, D. J. Chromosomal localization of the human P2Y(6) purinoceptor gene and phylogenetic analysis of the P2y purinoceptor family. Genomics 44: 127-130, 1997. [PubMed: 9286708] [Full Text: https://doi.org/10.1006/geno.1997.4841]

  9. Tai, C.-J., Kang, S. K., Cheng, K. W., Choi, K.-C., Nathwani, P. S., Leung, P. C. K. Expression and regulation of P2U-purinergic receptor in human granulosa-luteal cells. J. Clin. Endocr. Metab. 85: 1591-1597, 2000. [PubMed: 10770202] [Full Text: https://doi.org/10.1210/jcem.85.4.6558]


Contributors:
Ada Hamosh - updated : 10/13/2009
Ada Hamosh - updated : 1/23/2007
Patricia A. Hartz - updated : 1/30/2006
Patricia A. Hartz - updated : 3/7/2005
John A. Phillips, III - updated : 11/13/2000
John A. Phillips, III - updated : 10/2/2000
Jennifer P. Macke - updated : 10/30/1996

Creation Date:
Victor A. McKusick : 7/18/1994

Edit History:
alopez : 05/21/2019
alopez : 10/17/2016
terry : 08/03/2012
alopez : 10/22/2009
terry : 10/13/2009
alopez : 1/25/2007
terry : 1/23/2007
mgross : 1/30/2006
mgross : 3/7/2005
mgross : 12/7/2000
terry : 11/13/2000
mgross : 10/3/2000
terry : 10/2/2000
mgross : 4/8/1999
alopez : 3/18/1998
terry : 9/30/1997
jamie : 11/15/1996
jamie : 11/6/1996
jamie : 10/30/1996
jamie : 10/30/1996
mark : 3/31/1996
mark : 12/4/1995
mimadm : 7/30/1994
jason : 7/18/1994