Adenosine A3 receptor: Difference between revisions

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{{DISPLAYTITLE:Adenosine A<sub>3</sub> receptor}}
{{Infobox_gene}}
The '''adenosine A<sub>3</sub> receptor''', also known as '''ADORA3''', is an [[adenosine receptor]], but also denotes the human [[gene]] encoding it.


== Function ==


{{Wrongtitle|title=Adenosine A<sub>3</sub> receptor}}
Adenosine A<sub>3</sub> receptors are [[G protein-coupled receptor]]s that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions. It mediates a sustained cardioprotective function during [[cardiac ischemia]], it is involved in the inhibition of [[neutrophil degranulation]] in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death{{Citation needed|date=April 2015}}.
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Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potential in bronchial asthma (17,18).
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== Gene ==
{{GNF_Protein_box
Multiple transcript variants encoding different isoforms have been found for this gene.<ref name="entrez"/>
| image =
| image_source =
| PDB =  
| Name = Adenosine A3 receptor
| HGNCid = 268
| Symbol = ADORA3
| AltSymbols =; A3AR; AD026; RP11-552M11.7; bA552M11.5
| OMIM = 600445
| ECnumber = 
| Homologene = 550
| MGIid = 104847
| GeneAtlas_image1 = PBB_GE_ADORA3_206171_at_tn.png
| Function = {{GNF_GO|id=GO:0001584 |text = rhodopsin-like receptor activity}} {{GNF_GO|id=GO:0001613 |text = A3 adenosine receptor activity, G-protein coupled}} {{GNF_GO|id=GO:0004872 |text = receptor activity}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007190 |text = adenylate cyclase activation}} {{GNF_GO|id=GO:0008016 |text = regulation of heart contraction}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 140
    | Hs_Ensembl = ENSG00000121933
    | Hs_RefseqProtein = NP_000668
    | Hs_RefseqmRNA = NM_000677
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 111827493
    | Hs_GenLoc_end = 111908107
    | Hs_Uniprot = P33765
    | Mm_EntrezGene = 11542
    | Mm_Ensembl = ENSMUSG00000000562
    | Mm_RefseqmRNA = NM_009631
    | Mm_RefseqProtein = NP_033761
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 3
    | Mm_GenLoc_start = 106032479
    | Mm_GenLoc_end = 106036984
    | Mm_Uniprot = Q3U4C5
  }}
}}
The '''adenosine A<sub>3</sub> receptor''', also known as '''ADORA3''', is an [[adenosine receptor]], but also denotes the human [[gene]] encoding it.


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== Therapeutic implications ==
{{PBB_Summary
An adenosine A<sub>3</sub> receptor agonist (CF-101) is in clinical trials for the treatment of [[rheumatoid arthritis]].<ref name="pmid18050382"/>
| section_title =
In a mouse model of infarction the A<sub>3</sub> selective agonist [[CP-532,903]] protected against myocardial [[ischemia]] and [[reperfusion injury]].<ref name="pmid17906066"/>
| summary_text =  


==Function==
==Selective Ligands==
Adenosine A3 receptors are G-protein-coupled receptors that are involved in a variety of intracellular signaling pathways and physiological functions. It mediates a sustained cardioprotective function during [[cardiac ischemia]], it is involved in the inhibition of [[neutrophil degranulation]] in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death.  
A number of selective A<sub>3</sub> ligands are available.<ref name="pmid17150618"/><ref name="pmid17874974"/><ref name="pmid16793299"/><ref name="pmid16985166"/><ref name="pmid17382926"/><ref name="pmid18000937"/><ref name="pmid18255292"/><ref name="pmid17959910"/><ref name="pmid18424164"/><ref name="pmid18670113"/><ref name="pmid19077268"/><ref name="pmid18636149"/>


==Gene==
===Agonists/Positive Allosteric Modulators===
Multiple transcript variants encoding different isoforms have been found for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: ADORA3 adenosine A3 receptor| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=140| accessdate = }}</ref>
* 2-(1-Hexynyl)-N-methyladenosine
}}
* CF-101 (IB-MECA)
* CF-102
* 2-Cl-IB-MECA
* [[CP-532,903]]
* Inosine<ref>Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508491/pdf/1002849.pdf "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"]</ref>
* LUF-6000
* MRS-3558


==Therapeutic implications==
===Antagonists/Negative Allosteric Modulators===
* [[KF-26777]]
* MRS-545
* MRS-1191
* MRS-1220
* MRS-1334
* MRS-1523
* MRS-3777
* MRE-3005-F20
* MRE-3008-F20
* PSB-11
* OT-7999
* VUF-5574
* SSR161421<ref name="pmid23219796"/><ref name="pmid23219789"/>


An adenosine A3 receptor agonist (CF-101) is in clinical trials for the treatment of [[rheumatoid arthritis]].<ref name="pmid18050382">{{cite journal
===Inverse Agonists===
|author=Silverman MH, Strand V, Markovits D, ''et al''
* [[PSB-10]]
|title=Clinical Evidence for Utilization of the A3 Adenosine Receptor as a Target to Treat Rheumatoid Arthritis: Data from a Phase II Clinical Trial
|journal=J Rheumatol
|volume=
|issue=
|pages=
|year=2007
|pmid=18050382
|doi=
|url=http://www.jrheum.com/subscribers/07/13/1118.html
}}</ref>
In a mouse model of infarction the A3 selective agonist CP-532,903 protected against myocardial [[ischemia]] and [[reperfusion]] injury. <ref name="pmid17906066">{{cite journal
|author=Wan TC, Ge ZD, Tampo A, ''et al''
|title=The A3 adenosine receptor agonist CP-532,903 protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP sensitive potassium channel
|journal=J Pharmacol Exp Ther
|volume=
|issue=
|pages=
|year=2007
|pmid=17906066
|doi=10.1124/jpet.107.127480
|url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17906066
}}</ref>


==References==
==References==
{{reflist|2}}
{{reflist|colwidth=35em|refs=
 
<ref name="entrez">{{cite web | title = Entrez Gene: ADORA3 adenosine A3 receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=140| accessdate = }}</ref>
 
<ref name="pmid16793299">{{cite journal | vauthors = Kim SK, Gao ZG, Jeong LS, Jacobson KA | title = Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor | journal = Journal of Molecular Graphics & Modelling | volume = 25 | issue = 4 | pages = 562–77 |date=December 2006| pmid = 16793299 | doi = 10.1016/j.jmgm.2006.05.004 | url =  }}</ref>
 
<ref name="pmid16985166">{{cite journal | vauthors = Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA | title = Cl-IB-MECA Reduces Ischemia/Reperfusion Injury in Mice by Activating the A3 Adenosine Receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 319 | issue = 3 | pages = 1200–10 |date=December 2006| pmid = 16985166 | pmc = 2430759 | doi = 10.1124/jpet.106.111351 | url =  }}</ref>
 
<ref name="pmid17150618">{{cite journal | vauthors = Jeong LS, Lee HW, Jacobson KA, Lee SK, Chun MW | title = Development of potent and selective human A3 adenosine receptor agonists | journal = Nucleic Acids Symposium Series (2004) | volume = 49| issue = 49 | pages = 31–2 | year = 2005 | pmid = 17150618 | doi = 10.1093/nass/49.1.31 | url =  }}</ref>
 
<ref name="pmid17382926">{{cite journal | vauthors = Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V, Sheehan MJ, Reeves J, Wilson DJ | title = Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity | journal = European Journal of Pharmacology | volume = 564 | issue = 1-3 | pages = 219–25 |date=June 2007| pmid = 17382926 | doi = 10.1016/j.ejphar.2007.01.094 | url = | issn = }}</ref>
 
<ref name="pmid17874974">{{cite journal | vauthors = Gao ZG, Jacobson KA | title = Emerging adenosine receptor agonists | journal = Expert Opinion on Emerging Drugs | volume = 12 | issue = 3 | pages = 479–92 |date=September 2007| pmid = 17874974 | doi = 10.1517/14728214.12.3.479 | url =  }}</ref>
 
<ref name="pmid17906066">{{cite journal | vauthors = Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, Gross GJ, Kwok WM, Auchampach JA | title = The A3 adenosine receptor agonist CP-532,903 protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP sensitive potassium channel | journal = J. Pharmacol. Exp. Ther. | volume = 324 | issue = 1 | pages = 234–43 |date=January 2008| pmid = 17906066 | pmc = 2435594 | doi = 10.1124/jpet.107.127480 | url =  }}</ref>
 
<ref name="pmid17959910">{{cite journal | vauthors = Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ | title = Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells | journal = The FASEB Journal | volume = 22 | issue = 3 | pages = 850–60 |date=March 2008| pmid = 17959910 | doi = 10.1096/fj.07-8180com | url =  }}</ref>
 
<ref name="pmid18000937">{{cite journal | vauthors = Priego EM, Pérez-Pérez MJ, von Frijtag Drabbe Kuenzel JK, de Vries H, Ijzerman AP, Camarasa MJ, Martín-Santamaría S | title = Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding | journal = ChemMedChem | volume = 3 | issue = 1 | pages = 111–9 |date=January 2008| pmid = 18000937 | doi = 10.1002/cmdc.200700173 | url =  }}</ref>
 
<ref name="pmid18050382">{{cite journal | vauthors = Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P | title = Clinical evidence for utilization of the A<sub>3</sub> adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial | journal = J. Rheumatol. | volume = 35 | issue = 1 | pages = 41–8 |date=January 2008| pmid = 18050382 | doi = | url = http://www.jrheum.org/content/35/1/41.abstract }}</ref>
 
<ref name="pmid18255292">{{cite journal | vauthors = Jeong LS, Lee HW, Kim HO, Tosh DK, Pal S, Choi WJ, Gao ZG, Patel AR, Williams W, Jacobson KA, Kim HD | title = Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 5 | pages = 1612–6 |date=March 2008| pmid = 18255292 | doi = 10.1016/j.bmcl.2008.01.070 | url =  }}</ref>
 
<ref name="pmid18424164">{{cite journal | vauthors = Gao ZG, Jacobson KA | title = Translocation of Arrestin Induced by Human A3 Adenosine Receptor Ligands in an Engineered Cell Line: Comparison with G Protein-dependent Pathways | journal = Pharmacological Research : the Official Journal of the Italian Pharmacological Society | volume = 57 | issue = 4 | pages = 303–11 |date=April 2008| pmid = 18424164 | pmc = 2409065 | doi = 10.1016/j.phrs.2008.02.008 | url =  }}</ref>
 
<ref name="pmid18636149">{{cite journal | vauthors = Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, Perez-Liz G, Del Valle L, Fishman P | title = The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways | journal = International Journal of Oncology | volume = 33 | issue = 2 | pages = 287–95 |date=August 2008| pmid = 18636149 | doi = | url = http://www.spandidos-publications.com/ijo/article.jsp?article_id=ijo_33_2_287 }}</ref>
 
<ref name="pmid18670113">{{cite journal | vauthors = Miwatashi S, Arikawa Y, Matsumoto T, Uga K, Kanzaki N, Imai YN, Ohkawa S | title = Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists | journal = Chemical & Pharmaceutical Bulletin | volume = 56 | issue = 8 | pages = 1126–37 |date=August 2008| pmid = 18670113 | doi = 10.1248/cpb.56.1126| url = http://joi.jlc.jst.go.jp/JST.JSTAGE/cpb/56.1126?from=PubMed  }}{{dead link|date=May 2009}}</ref>
 
<ref name="pmid19077268">{{cite journal | vauthors = Gao ZG, Ye K, Göblyös A, Ijzerman AP, Jacobson KA | title = Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000 | journal = BMC Pharmacology | volume = 8 | issue = | page = 20 | year = 2008 | pmid = 19077268 | pmc = 2625337 | doi = 10.1186/1471-2210-8-20 | url =  }}</ref>
 
<ref name="pmid23219796">{{cite journal | vauthors = Mikus EG, Szeredi J, Boer K, Tímári G, Finet M, Aranyi P, Galzin AM | title = Evaluation of SSR161421, a novel orally active adenosine A(3) receptor antagonist on pharmacology models | journal = Eur. J. Pharmacol. | volume = 699 | issue = 1-3 | pages = 172–179 |date=December 2012| pmid = 23219796 | doi = 10.1016/j.ejphar.2012.11.049 | url = }}</ref>
 
<ref name="pmid23219789">{{cite journal | vauthors = Mikus EG, Boér K, Timári G, Urbán-Szabó K, Kapui Z, Szeredi J, Gerber K, Szabó T, Bátori S, Finet M, Arányi P, Galzin AM | title = Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo | journal = Eur. J. Pharmacol. | volume = 699 | issue = 1-3 | pages = 62–66 |date=December 2012| pmid = 23219789 | doi = 10.1016/j.ejphar.2012.11.046 }}</ref>
 
}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin |colwidth=35em}}
{{PBB_Further_reading
* {{cite journal  | author=Klotz KN |title=Adenosine receptors and their ligands |journal=Naunyn Schmiedebergs Arch. Pharmacol. |volume=362 |issue= 4–5 |pages= 382–91 |year= 2001 |pmid= 11111832 |doi=10.1007/s002100000315 }}
| citations =
* {{cite journal  | vauthors=Monitto CL, Levitt RC, DiSilvestre D, Holroyd KJ |title=Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p |journal=Genomics |volume=26 |issue= 3 |pages= 637–8 |year= 1995 |pmid= 7607699 |doi=10.1016/0888-7543(95)80194-Q }}
*{{cite journal  | author=Klotz KN |title=Adenosine receptors and their ligands. |journal=Naunyn Schmiedebergs Arch. Pharmacol. |volume=362 |issue= 4-5 |pages= 382-91 |year= 2001 |pmid= 11111832 |doi=  }}
* {{cite journal  | vauthors=Salvatore CA, Jacobson MA, Taylor HE |title=Molecular cloning and characterization of the human A3 adenosine receptor |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 21 |pages= 10365–9 |year= 1993 |pmid= 8234299 |doi=10.1073/pnas.90.21.10365  | pmc=47775 |display-authors=etal}}
*{{cite journal  | author=Monitto CL, Levitt RC, DiSilvestre D, Holroyd KJ |title=Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p. |journal=Genomics |volume=26 |issue= 3 |pages= 637-8 |year= 1995 |pmid= 7607699 |doi=  }}
* {{cite journal  | vauthors=Sajjadi FG, Firestein GS |title=cDNA cloning and sequence analysis of the human A3 adenosine receptor |journal=Biochim. Biophys. Acta |volume=1179 |issue= 1 |pages= 105–7 |year= 1993 |pmid= 8399349 |doi=10.1016/0167-4889(93)90077-3 }}
*{{cite journal  | author=Salvatore CA, Jacobson MA, Taylor HE, ''et al.'' |title=Molecular cloning and characterization of the human A3 adenosine receptor. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 21 |pages= 10365-9 |year= 1993 |pmid= 8234299 |doi=  }}
* {{cite journal  | vauthors=Murrison EM, Goodson SJ, Edbrooke MR, Harris CA |title=Cloning and characterisation of the human adenosine A3 receptor gene |journal=FEBS Lett. |volume=384 |issue= 3 |pages= 243–6 |year= 1996 |pmid= 8617363 |doi=10.1016/0014-5793(96)00324-9 }}
*{{cite journal  | author=Sajjadi FG, Firestein GS |title=cDNA cloning and sequence analysis of the human A3 adenosine receptor. |journal=Biochim. Biophys. Acta |volume=1179 |issue= 1 |pages= 105-7 |year= 1993 |pmid= 8399349 |doi=  }}
* {{cite journal  | vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 }}
*{{cite journal  | author=Murrison EM, Goodson SJ, Edbrooke MR, Harris CA |title=Cloning and characterisation of the human adenosine A3 receptor gene. |journal=FEBS Lett. |volume=384 |issue= 3 |pages= 243-6 |year= 1996 |pmid= 8617363 |doi=  }}
* {{cite journal  | vauthors=Bouma MG, Jeunhomme TM, Boyle DL |title=Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors |journal=J. Immunol. |volume=158 |issue= 11 |pages= 5400–8 |year= 1997 |pmid= 9164961 |doi=  |display-authors=etal}}
*{{cite journal  | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791-806 |year= 1997 |pmid= 8889548 |doi=  }}
* {{cite journal  | vauthors=Atkinson MR, Townsend-Nicholson A, Nicholl JK |title=Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene |journal=Neurosci. Res. |volume=29 |issue= 1 |pages= 73–9 |year= 1998 |pmid= 9293494 |doi=10.1016/S0168-0102(97)00073-4  |display-authors=etal}}
*{{cite journal  | author=Bouma MG, Jeunhomme TM, Boyle DL, ''et al.'' |title=Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors. |journal=J. Immunol. |volume=158 |issue= 11 |pages= 5400-8 |year= 1997 |pmid= 9164961 |doi=  }}
* {{cite journal  | vauthors=Palmer TM, Harris CA, Coote J, Stiles GL |title=Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor |journal=Mol. Pharmacol. |volume=52 |issue= 4 |pages= 632–40 |year= 1997 |pmid= 9380026 |doi=  }}
*{{cite journal  | author=Atkinson MR, Townsend-Nicholson A, Nicholl JK, ''et al.'' |title=Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene. |journal=Neurosci. Res. |volume=29 |issue= 1 |pages= 73-9 |year= 1998 |pmid= 9293494 |doi= }}
* {{cite journal  | vauthors=Liang BT, Jacobson KA |title=A physiological role of the adenosine A3 receptor: Sustained cardioprotection |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 12 |pages= 6995–9 |year= 1998 |pmid= 9618527 |doi=10.1073/pnas.95.12.6995  | pmc=22715  }}
*{{cite journal  | author=Palmer TM, Harris CA, Coote J, Stiles GL |title=Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor. |journal=Mol. Pharmacol. |volume=52 |issue= 4 |pages= 632-40 |year= 1997 |pmid= 9380026 |doi=  }}
* {{cite journal  | vauthors=Dougherty C, Barucha J, Schofield PR |title=Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor |journal=FASEB J. |volume=12 |issue= 15 |pages= 1785–92 |year= 1999 |pmid= 9837869 |doi=  |display-authors=etal}}
*{{cite journal  | author=Liang BT, Jacobson KA |title=A physiological role of the adenosine A3 receptor: sustained cardioprotection. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 12 |pages= 6995-9 |year= 1998 |pmid= 9618527 |doi= }}
* {{cite journal  | vauthors=Murphy WJ, Eizirik E, Johnson WE |title=Molecular phylogenetics and the origins of placental mammals |journal=Nature |volume=409 |issue= 6820 |pages= 614–8 |year= 2001 |pmid= 11214319 |doi= 10.1038/35054550 |display-authors=etal}}
*{{cite journal  | author=Dougherty C, Barucha J, Schofield PR, ''et al.'' |title=Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor. |journal=FASEB J. |volume=12 |issue= 15 |pages= 1785-92 |year= 1999 |pmid= 9837869 |doi=  }}
* {{cite journal  | vauthors=Gao ZG, Chen A, Barak D |title=Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor |journal=J. Biol. Chem. |volume=277 |issue= 21 |pages= 19056–63 |year= 2002 |pmid= 11891221 |doi= 10.1074/jbc.M110960200 |display-authors=etal}}
*{{cite journal  | author=Murphy WJ, Eizirik E, Johnson WE, ''et al.'' |title=Molecular phylogenetics and the origins of placental mammals. |journal=Nature |volume=409 |issue= 6820 |pages= 614-8 |year= 2001 |pmid= 11214319 |doi= 10.1038/35054550 }}
* {{cite journal  | vauthors=Broussas M, Cornillet-Lefèbvre P, Potron G, Nguyên P |title=Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor |journal=Thromb. Haemost. |volume=88 |issue= 1 |pages= 123–30 |year= 2003 |pmid= 12152652 |doi=  }}
*{{cite journal  | author=Gao ZG, Chen A, Barak D, ''et al.'' |title=Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor. |journal=J. Biol. Chem. |volume=277 |issue= 21 |pages= 19056-63 |year= 2002 |pmid= 11891221 |doi= 10.1074/jbc.M110960200 }}
* {{cite journal  | vauthors=Merighi S, Mirandola P, Milani D |title=Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells |journal=J. Invest. Dermatol. |volume=119 |issue= 4 |pages= 923–33 |year= 2002 |pmid= 12406340 |doi= 10.1046/j.1523-1747.2002.00111.x |display-authors=etal}}
*{{cite journal  | author=Broussas M, Cornillet-Lefèbvre P, Potron G, Nguyên P |title=Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor. |journal=Thromb. Haemost. |volume=88 |issue= 1 |pages= 123-30 |year= 2003 |pmid= 12152652 |doi=  }}
* {{cite journal  | vauthors=Trincavelli ML, Tuscano D, Marroni M |title=A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation |journal=Mol. Pharmacol. |volume=62 |issue= 6 |pages= 1373–84 |year= 2002 |pmid= 12435805 |doi=10.1124/mol.62.6.1373 |display-authors=etal}}
*{{cite journal  | author=Merighi S, Mirandola P, Milani D, ''et al.'' |title=Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. |journal=J. Invest. Dermatol. |volume=119 |issue= 4 |pages= 923-33 |year= 2002 |pmid= 12406340 |doi= 10.1046/j.1523-1747.2002.00111.x }}
* {{cite journal  | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |display-authors=etal}}
*{{cite journal  | author=Trincavelli ML, Tuscano D, Marroni M, ''et al.'' |title=A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation. |journal=Mol. Pharmacol. |volume=62 |issue= 6 |pages= 1373-84 |year= 2002 |pmid= 12435805 |doi=  }}
* {{cite journal  | vauthors=Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I |title=Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors |journal=Circ. Res. |volume=92 |issue= 5 |pages= 485–92 |year= 2003 |pmid= 12600879 |doi= 10.1161/01.RES.0000061572.10929.2D }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal  | vauthors=Gao ZG, Kim SK, Gross AS |title=Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor |journal=Mol. Pharmacol. |volume=63 |issue= 5 |pages= 1021–31 |year= 2003 |pmid= 12695530 |doi=10.1124/mol.63.5.1021 |display-authors=etal}}
*{{cite journal  | author=Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I |title=Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. |journal=Circ. Res. |volume=92 |issue= 5 |pages= 485-92 |year= 2003 |pmid= 12600879 |doi= 10.1161/01.RES.0000061572.10929.2D }}
*{{cite journal  | author=Gao ZG, Kim SK, Gross AS, ''et al.'' |title=Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor. |journal=Mol. Pharmacol. |volume=63 |issue= 5 |pages= 1021-31 |year= 2003 |pmid= 12695530 |doi=  }}
}}
{{refend}}
{{refend}}
==External links==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2172 | title = Adenosine Receptors: A<sub>3</sub>  | accessdate = | date = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | language = | quote = }}
* {{UCSC gene info|ADORA3}}


{{G protein-coupled receptors}}
{{G protein-coupled receptors}}
[[Category:Adrenergic receptors‎]]
{{Adenosinergics}}
[[Category:Signal transduction]]


{{WH}}
[[Category:Adenosine receptors]]
{{WS}}

Revision as of 19:03, 29 August 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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The adenosine A3 receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it.

Function

Adenosine A3 receptors are G protein-coupled receptors that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions. It mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death[citation needed]. Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potential in bronchial asthma (17,18).

Gene

Multiple transcript variants encoding different isoforms have been found for this gene.[1]

Therapeutic implications

An adenosine A3 receptor agonist (CF-101) is in clinical trials for the treatment of rheumatoid arthritis.[2] In a mouse model of infarction the A3 selective agonist CP-532,903 protected against myocardial ischemia and reperfusion injury.[3]

Selective Ligands

A number of selective A3 ligands are available.[4][5][6][7][8][9][10][11][12][13][14][15]

Agonists/Positive Allosteric Modulators

  • 2-(1-Hexynyl)-N-methyladenosine
  • CF-101 (IB-MECA)
  • CF-102
  • 2-Cl-IB-MECA
  • CP-532,903
  • Inosine[16]
  • LUF-6000
  • MRS-3558

Antagonists/Negative Allosteric Modulators

  • KF-26777
  • MRS-545
  • MRS-1191
  • MRS-1220
  • MRS-1334
  • MRS-1523
  • MRS-3777
  • MRE-3005-F20
  • MRE-3008-F20
  • PSB-11
  • OT-7999
  • VUF-5574
  • SSR161421[17][18]

Inverse Agonists

References

  1. ↑ "Entrez Gene: ADORA3 adenosine A3 receptor".
  2. ↑ Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P (January 2008). "Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial". J. Rheumatol. 35 (1): 41–8. PMID 18050382.
  3. ↑ Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, Gross GJ, Kwok WM, Auchampach JA (January 2008). "The A3 adenosine receptor agonist CP-532,903 protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP sensitive potassium channel". J. Pharmacol. Exp. Ther. 324 (1): 234–43. doi:10.1124/jpet.107.127480. PMC 2435594. PMID 17906066.
  4. ↑ Jeong LS, Lee HW, Jacobson KA, Lee SK, Chun MW (2005). "Development of potent and selective human A3 adenosine receptor agonists". Nucleic Acids Symposium Series (2004). 49 (49): 31–2. doi:10.1093/nass/49.1.31. PMID 17150618.
  5. ↑ Gao ZG, Jacobson KA (September 2007). "Emerging adenosine receptor agonists". Expert Opinion on Emerging Drugs. 12 (3): 479–92. doi:10.1517/14728214.12.3.479. PMID 17874974.
  6. ↑ Kim SK, Gao ZG, Jeong LS, Jacobson KA (December 2006). "Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor". Journal of Molecular Graphics & Modelling. 25 (4): 562–77. doi:10.1016/j.jmgm.2006.05.004. PMID 16793299.
  7. ↑ Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (December 2006). "Cl-IB-MECA Reduces Ischemia/Reperfusion Injury in Mice by Activating the A3 Adenosine Receptor". The Journal of Pharmacology and Experimental Therapeutics. 319 (3): 1200–10. doi:10.1124/jpet.106.111351. PMC 2430759. PMID 16985166.
  8. ↑ Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V, Sheehan MJ, Reeves J, Wilson DJ (June 2007). "Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity". European Journal of Pharmacology. 564 (1–3): 219–25. doi:10.1016/j.ejphar.2007.01.094. PMID 17382926.
  9. ↑ Priego EM, Pérez-Pérez MJ, von Frijtag Drabbe Kuenzel JK, de Vries H, Ijzerman AP, Camarasa MJ, Martín-Santamaría S (January 2008). "Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding". ChemMedChem. 3 (1): 111–9. doi:10.1002/cmdc.200700173. PMID 18000937.
  10. ↑ Jeong LS, Lee HW, Kim HO, Tosh DK, Pal S, Choi WJ, Gao ZG, Patel AR, Williams W, Jacobson KA, Kim HD (March 2008). "Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (5): 1612–6. doi:10.1016/j.bmcl.2008.01.070. PMID 18255292.
  11. ↑ Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ (March 2008). "Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells". The FASEB Journal. 22 (3): 850–60. doi:10.1096/fj.07-8180com. PMID 17959910.
  12. ↑ Gao ZG, Jacobson KA (April 2008). "Translocation of Arrestin Induced by Human A3 Adenosine Receptor Ligands in an Engineered Cell Line: Comparison with G Protein-dependent Pathways". Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 57 (4): 303–11. doi:10.1016/j.phrs.2008.02.008. PMC 2409065. PMID 18424164.
  13. ↑ Miwatashi S, Arikawa Y, Matsumoto T, Uga K, Kanzaki N, Imai YN, Ohkawa S (August 2008). "Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists". Chemical & Pharmaceutical Bulletin. 56 (8): 1126–37. doi:10.1248/cpb.56.1126. PMID 18670113.[dead link]
  14. ↑ Gao ZG, Ye K, Göblyös A, Ijzerman AP, Jacobson KA (2008). "Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000". BMC Pharmacology. 8: 20. doi:10.1186/1471-2210-8-20. PMC 2625337. PMID 19077268.
  15. ↑ Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, Perez-Liz G, Del Valle L, Fishman P (August 2008). "The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways". International Journal of Oncology. 33 (2): 287–95. PMID 18636149.
  16. ↑ Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"
  17. ↑ Mikus EG, Szeredi J, Boer K, Tímári G, Finet M, Aranyi P, Galzin AM (December 2012). "Evaluation of SSR161421, a novel orally active adenosine A(3) receptor antagonist on pharmacology models". Eur. J. Pharmacol. 699 (1–3): 172–179. doi:10.1016/j.ejphar.2012.11.049. PMID 23219796.
  18. ↑ Mikus EG, Boér K, Timári G, Urbán-Szabó K, Kapui Z, Szeredi J, Gerber K, Szabó T, Bátori S, Finet M, Arányi P, Galzin AM (December 2012). "Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo". Eur. J. Pharmacol. 699 (1–3): 62–66. doi:10.1016/j.ejphar.2012.11.046. PMID 23219789.

Further reading

External links

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