ADCY2: Difference between revisions

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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Adenylyl cyclase type 2''' is an [[enzyme]] typically expressed in the brain of humans, that is encoded by the ''ADCY2'' [[gene]].<ref name="pmid1427768">{{cite journal | vauthors = Stengel D, Parma J, Gannagé MH, Roeckel N, Mattei MG, Barouki R, Hanoune J | title = Different chromosomal localization of two adenylyl cyclase genes expressed in human brain | journal = Human Genetics | volume = 90 | issue = 1–2 | pages = 126–30 | date = Dec 1992 | pmid = 1427768 | pmc =  | doi = 10.1007/BF00210755 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ADCY2 adenylyl cyclase 2 (brain)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=108| accessdate = }}</ref> It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains.<ref name = "UniProt_Q08462">{{cite web|title=Adenylate cyclase type 2|url=https://www.uniprot.org/uniprot/Q08462#section_comments|publisher=UniProt Consortium|accessdate=28 May 2014}}</ref> ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.<ref name = "UniProt_Q08462"/>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image = PBB_Protein_ADCY2_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1ab8.
| PDB = {{PDB2|1ab8}}, {{PDB2|1azs}}, {{PDB2|1cjk}}, {{PDB2|1cjt}}, {{PDB2|1cju}}, {{PDB2|1cjv}}, {{PDB2|1cs4}}, {{PDB2|1cul}}, {{PDB2|1tl7}}, {{PDB2|1u0h}}, {{PDB2|2gvd}}, {{PDB2|2gvz}}
| Name = Adenylate cyclase 2 (brain)
| HGNCid = 233
| Symbol = ADCY2
| AltSymbols =; FLJ16822; FLJ45092; HBAC2; KIAA1060; MGC133314
| OMIM = 103071
| ECnumber = 
| Homologene = 75133
| MGIid = 99676
| GeneAtlas_image1 = PBB_GE_ADCY2_213217_at_tn.png
| GeneAtlas_image2 = PBB_GE_ADCY2_213219_at_tn.png
| GeneAtlas_image3 = PBB_GE_ADCY2_217687_at_tn.png
| Function = {{GNF_GO|id=GO:0000287 |text = magnesium ion binding}} {{GNF_GO|id=GO:0004016 |text = adenylate cyclase activity}}
| Component = {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006171 |text = cAMP biosynthetic process}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 108
    | Hs_Ensembl = ENSG00000078295
    | Hs_RefseqProtein = NP_065433
    | Hs_RefseqmRNA = NM_020546
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 5
    | Hs_GenLoc_start = 7449345
    | Hs_GenLoc_end = 7883194
    | Hs_Uniprot = Q08462
    | Mm_EntrezGene = 210044
    | Mm_Ensembl = ENSMUSG00000021536
    | Mm_RefseqmRNA = NM_153534
    | Mm_RefseqProtein = NP_705762
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 13
    | Mm_GenLoc_start = 69087426
    | Mm_GenLoc_end = 69466728
    | Mm_Uniprot = Q3V1Q3
  }}
}}
'''Adenylate cyclase 2 (brain)''', also known as '''ADCY2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ADCY2 adenylate cyclase 2 (brain)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=108| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
Structurally, ADCY2 are transmembrane proteins with twelve transmembrane segments. The protein is organized with six transmembrane segments followed by the C1 cytoplasmic domain. Then another six membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site.
{{PBB_Summary
 
| section_title =  
This structure displays significant homology with human brain adenylyl cyclase 1(HBA C1 or [[ADCY1]]) in the highly conserved adenylyl cyclases domain found in the 3’ cytoplasmic domain of all mammalian adenylyl cyclases. Outside this domain homology is not similar suggesting that this corresponding mRNA originates from a different gene. In situ hybridization confirms a heterogeneous population of adenylyl cyclase mRNAs is expressed in the brain.<ref>{{cite journal | vauthors = Stengel D, Parma J, Gannagé MH, Roeckel N, Mattei MG, Barouki R, Hanoune J | title = Different chromosomal localization of two adenylyl cyclase genes expressed in human brain | journal = Human Genetics | volume = 90 | issue = 1–2 | pages = 126–30 | date = Sep–Oct 1992 | doi = 10.1007/BF00210755 | pmid = 1427768 }}</ref>
| summary_text = This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This enzyme is insensitive to Ca(2+)/calmodulin, and is stimulated by the G protein beta and gamma subunit complex.<ref name="entrez">{{cite web | title = Entrez Gene: ADCY2 adenylate cyclase 2 (brain)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=108| accessdate = }}</ref>
 
}}
== Function ==
 
This gene encodes a member of the family of [[adenylyl cyclase]]s, which are membrane-associated enzymes that catalyze the formation of the secondary messenger [[cyclic adenosine monophosphate]] (cAMP) from ATP. ADCY2 has also been found to accelerate phosphor-acidification, along with glycogen synthesis and breakdown.<ref name="pmid24797538">{{cite journal | vauthors = Li YX, Jin HG, Yan CG, Ren CY, Jiang CJ, Jin CD, Seo KS, Jin X | title = Molecular cloning, sequence identification, and gene expression analysis of bovine ADCY2 gene | journal = Molecular Biology Reports | volume = 41 | issue = 6 | pages = 3561–8 | date = Jun 2014 | pmid = 24797538 | doi = 10.1007/s11033-014-3167-9 }}</ref> This enzyme is insensitive to Ca<sup>2+</sup>/[[calmodulin]], and is stimulated by the G protein beta and gamma subunit complex.<ref name="entrez"/> Therefore, ADCY2 is highly regulated by G-proteins, calcium, calmodulin, pyrophosphate, and post-translational modifications.
 
Recently, it has been discover that ADCY2 can activated by a Raf kinase-mediated serine phosphorylation.<ref>{{cite journal | vauthors = Ding Q, Gros R, Gray ID, Taussig R, Ferguson SS, Feldman RD | title = Raf kinase activation of adenylyl cyclases: isoform-selective regulation | journal = Molecular Pharmacology | volume = 66 | issue = 4 | pages = 921–8 | date = Oct 2004 | doi = 10.1124/mol.66.4.921| pmid = 15385642 }}</ref> In aggregate, Raf kinase associates with adenylyl cyclases and is isoform-selective, which includes adenylyl cyclase type 2.
In human embryonic kidney cells, ADCY2 is stimulated by activation of Gq-coupled muscarinic receptors through [[protein kinase C]] (PKC) to generate localized cAMP. Once the agonist binding to the Gq-coupled muscarinic receptor, A-kinase-anchoring protein ([[AKAP]]) recruits PKC to activate ADCY2 to produce cAMP. The cAMP formed is degraded by [[phosphodiesterase 4]] (PDE4) activated by an AKAP-anchored protein kinase A.<ref name="pmid23889134">{{cite journal | vauthors = Shen JX, Cooper DM | title = AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex | journal = The Biochemical Journal | volume = 455 | issue = 1 | pages = 47–56 | date = Oct 2013 | pmid = 23889134 | pmc = 3968274 | doi = 10.1042/BJ20130359 }}</ref>
 
== Clinical significance ==
 
Polymorphisms of the ''ADCY2'' gene have been associated with [[COPD]] and lung function.<ref name="ichg2011">{{cite web|title=Testing GWAS SNPs for COPD and lung function in a Polish cohort with severe COPD |url=http://www.ichg2011.org/cgi-bin/showdetail.pl?absno=11075 |accessdate=2012-12-30 |deadurl=yes |archiveurl=https://web.archive.org/web/20140529051806/http://www.ichg2011.org/cgi-bin/showdetail.pl?absno=11075 |archivedate=2014-05-29 }}</ref>
 
Perturbations in adenylyl cyclase activity have been implicated in alcohol and opioid addiction and is associated with human diseases, including [[thyroid adenoma]], [[Anthrax]], [[precocious puberty]] in males and [[chondrodysplasia punctata]] diseases.<ref>{{cite web|title=Adenylate Cyclase 2 (Brain)|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADCY2|publisher=Weizmann Institute of Science|accessdate=28 May 2014}}</ref> During these diseases, ADCY2 undergoes a super-related pathway where [[protein kinase A]] (PKA) activation occurs in glucagon signaling and IP3 signaling. This enzyme may play a role in bipolar disorder along with other brain-expressed genes including NCALD, WDR60, SCN7A, and SPAG16.<ref name="pmid24387768">{{cite journal | vauthors = Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, Parikh SV, De Luca V, Tozzi F, Muglia P, Forte J, McQuillin A, Hu P, Gurling HM, Kennedy JL, McGuffin P, Farmer A, Strauss J, Vincent JB | title = Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1 | journal = BMC Medical Genetics | volume = 15 | issue =  | pages = 2 | year = 2014 | pmid = 24387768 | pmc = 3901032 | doi = 10.1186/1471-2350-15-2 }}</ref>
 
== Interactive pathway map ==
{{NicotineDopaminergicActivity_WP1602|highlight=ADCY2}}
{{clear}}
 
==Model organisms==
[[Model organism]]s have been used in the study of ADCY2 function. A conditional [[knockout mouse]] line called ''Adcy2<sup>tm1a(KOMP)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }}</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Adcy2#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref><ref name="pmid23870131">{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, ((Sanger Institute Mouse Genetics Project)), Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | year = 2013 | pmid = 23870131 | doi = 10.1016/j.cell.2013.06.022 | pmc=3717207}}</ref> Additional screens performed:  - In-depth immunological phenotyping<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Adcy2&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref> - in-depth bone and cartilage phenotyping<ref name="obcd_ref">{{cite web |url=http://www.boneandcartilage.com/ |title=OBCD Consortium}}</ref>  
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: left;" |
|+ ''Adcy2'' knockout mouse phenotype
|-
! Characteristic!! Phenotype
|-
| colspan=2; style="text-align: center;" | All data available at.<ref name="IMPCsearch_ref"/><ref name="iii_ref" />
|-
| Insulin || bgcolor="#488ED3"|Normal
 
|-
| Homozygous viability at P14 || bgcolor="#488ED3"|Normal
 
|-
| Homozygous Fertility || bgcolor="#488ED3"|Normal
 
|-
| Body weight || bgcolor="#488ED3"|Normal
 
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
 
|-
| Grip strength || bgcolor="#488ED3"|Normal
 
|-
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal
 
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
 
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal
 
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#488ED3"|Normal
 
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal
 
|-
| Eye morphology || bgcolor="#488ED3"|Normal
 
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
 
|-
| ''[[Haematology]]'' 16 Weeks || bgcolor="#488ED3"|Normal
 
|-
| Peripheral blood leukocytes 16 Weeks || bgcolor="#488ED3"|Normal
 
|-
| Heart weight || bgcolor="#488ED3"|Normal
 
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal
 
|-
| Spleen Immunophenotyping || bgcolor="#488ED3"|Normal
 
|-
| Mesenteric Lymph Node Immunophenotyping || bgcolor="#488ED3"|Normal
 
|-
| Epidermal Immune Composition || bgcolor="#488ED3"|Normal
 
|-
|}


==References==
==References==
{{reflist|2}}
{{reflist|35em}}
==Further reading==
 
{{refbegin | 2}}
 
{{PBB_Further_reading
==External links==
| citations =  
* {{UCSC gene info|ADCY2}}
*{{cite journal  | author=Stengel D, Parma J, Gannagé MH, ''et al.'' |title=Different chromosomal localization of two adenylyl cyclase genes expressed in human brain. |journal=Hum. Genet. |volume=90 |issue= 1-2 |pages= 126-30 |year= 1992 |pmid= 1427768 |doi=  }}
 
*{{cite journal | author=Gaudin C, Homcy CJ, Ishikawa Y |title=Mammalian adenylyl cyclase family members are randomly located on different chromosomes. |journal=Hum. Genet. |volume=94 |issue= 5 |pages= 527-9 |year= 1994 |pmid= 7959689 |doi= }}
== Further reading ==
*{{cite journal | author=Andersson B, Wentland MA, Ricafrente JY, ''et al.'' |title=A "double adaptor" method for improved shotgun library construction. |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107-13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 }}
{{refbegin|35em}}
*{{cite journal | author=Whisnant RE, Gilman AG, Dessauer CW |title=Interaction of the two cytosolic domains of mammalian adenylyl cyclase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue= 13 |pages= 6621-5 |year= 1996 |pmid= 8692867 |doi= }}
* {{cite journal | vauthors = Gaudin C, Homcy CJ, Ishikawa Y | title = Mammalian adenylyl cyclase family members are randomly located on different chromosomes | journal = Human Genetics | volume = 94 | issue = 5 | pages = 527–9 | date = Nov 1994 | pmid = 7959689 | doi = 10.1007/BF00211020 }}
*{{cite journal | author=Yu W, Andersson B, Worley KC, ''et al.'' |title=Large-scale concatenation cDNA sequencing. |journal=Genome Res. |volume=7 |issue= 4 |pages= 353-8 |year= 1997 |pmid= 9110174 |doi= }}
* {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = Apr 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
*{{cite journal | author=Sunahara RK, Dessauer CW, Whisnant RE, ''et al.'' |title=Interaction of Gsalpha with the cytosolic domains of mammalian adenylyl cyclase. |journal=J. Biol. Chem. |volume=272 |issue= 35 |pages= 22265-71 |year= 1997 |pmid= 9268375 |doi= }}
* {{cite journal | vauthors = Whisnant RE, Gilman AG, Dessauer CW | title = Interaction of the two cytosolic domains of mammalian adenylyl cyclase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 13 | pages = 6621–5 | date = Jun 1996 | pmid = 8692867 | pmc = 39075 | doi = 10.1073/pnas.93.13.6621 }}
*{{cite journal | author=Barcova M, Speth C, Kacani L, ''et al.'' |title=Involvement of adenylate cyclase and p70(S6)-kinase activation in IL-10 up-regulation in human monocytes by gp41 envelope protein of human immunodeficiency virus type 1. |journal=Pflugers Arch. |volume=437 |issue= 4 |pages= 538-46 |year= 1999 |pmid= 10089566 |doi= }}
* {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = Apr 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
*{{cite journal | author=Kikuno R, Nagase T, Ishikawa K, ''et al.'' |title=Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. |journal=DNA Res. |volume=6 |issue= 3 |pages= 197-205 |year= 1999 |pmid= 10470851 |doi= }}
* {{cite journal | vauthors = Sunahara RK, Dessauer CW, Whisnant RE, Kleuss C, Gilman AG | title = Interaction of Gsalpha with the cytosolic domains of mammalian adenylyl cyclase | journal = The Journal of Biological Chemistry | volume = 272 | issue = 35 | pages = 22265–71 | date = Aug 1997 | pmid = 9268375 | doi = 10.1074/jbc.272.35.22265 }}
*{{cite journal | author=Speth C, Joebstl B, Barcova M, Dierich MP |title=HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones. |journal=AIDS |volume=14 |issue= 6 |pages= 629-36 |year= 2000 |pmid= 10807185 |doi= }}
* {{cite journal | vauthors = Barcova M, Speth C, Kacani L, Uberall F, Stoiber H, Dierich MP | title = Involvement of adenylate cyclase and p70(S6)-kinase activation in IL-10 up-regulation in human monocytes by gp41 envelope protein of human immunodeficiency virus type 1 | journal = Pflügers Archiv | volume = 437 | issue = 4 | pages = 538–46 | date = Mar 1999 | pmid = 10089566 | doi = 10.1007/s004240050815 }}
*{{cite journal | author=Patke CL, Shearer WT |title=gp120- and TNF-alpha-induced modulation of human B cell function: proliferation, cyclic AMP generation, Ig production, and B-cell receptor expression. |journal=J. Allergy Clin. Immunol. |volume=105 |issue= 5 |pages= 975-82 |year= 2000 |pmid= 10808179 |doi= 10.1067/mai.2000.105315 }}
* {{cite journal | vauthors = Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research | volume = 6 | issue = 3 | pages = 197–205 | date = Jun 1999 | pmid = 10470851 | doi = 10.1093/dnares/6.3.197 }}
*{{cite journal | author=Patrizio M, Colucci M, Levi G |title=Human immunodeficiency virus type 1 Tat protein decreases cyclic AMP synthesis in rat microglia cultures. |journal=J. Neurochem. |volume=77 |issue= 2 |pages= 399-407 |year= 2001 |pmid= 11299302 |doi= }}
* {{cite journal | vauthors = Speth C, Joebstl B, Barcova M, Dierich MP | title = HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones | journal = AIDS | volume = 14 | issue = 6 | pages = 629–36 | date = Apr 2000 | pmid = 10807185 | doi = 10.1097/00002030-200004140-00001 }}
*{{cite journal | author=Côté M, Guillon G, Payet MD, Gallo-Payet N |title=Expression and regulation of adenylyl cyclase isoforms in the human adrenal gland. |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue= 9 |pages= 4495-503 |year= 2001 |pmid= 11549699 |doi= }}
* {{cite journal | vauthors = Patke CL, Shearer WT | title = gp120- and TNF-alpha-induced modulation of human B cell function: proliferation, cyclic AMP generation, Ig production, and B-cell receptor expression | journal = The Journal of Allergy and Clinical Immunology | volume = 105 | issue = 5 | pages = 975–82 | date = May 2000 | pmid = 10808179 | doi = 10.1067/mai.2000.105315 }}
*{{cite journal | author=Speth C, Schabetsberger T, Mohsenipour I, ''et al.'' |title=Mechanism of human immunodeficiency virus-induced complement expression in astrocytes and neurons. |journal=J. Virol. |volume=76 |issue= 7 |pages= 3179-88 |year= 2002 |pmid= 11884542 |doi= }}
* {{cite journal | vauthors = Patrizio M, Colucci M, Levi G | title = Human immunodeficiency virus type 1 Tat protein decreases cyclic AMP synthesis in rat microglia cultures | journal = Journal of Neurochemistry | volume = 77 | issue = 2 | pages = 399–407 | date = Apr 2001 | pmid = 11299302 | doi = 10.1046/j.1471-4159.2001.00249.x }}
*{{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 = Côté M, Guillon G, Payet MD, Gallo-Payet N | title = Expression and regulation of adenylyl cyclase isoforms in the human adrenal gland | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 9 | pages = 4495–503 | date = Sep 2001 | pmid = 11549699 | doi = 10.1210/jc.86.9.4495 }}
*{{cite journal | author=Ludwig MG, Seuwen K |title=Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms. |journal=J. Recept. Signal Transduct. Res. |volume=22 |issue= 1-4 |pages= 79-110 |year= 2003 |pmid= 12503609 |doi=  }}
* {{cite journal | vauthors = Speth C, Schabetsberger T, Mohsenipour I, Stöckl G, Würzner R, Stoiber H, Lass-Flörl C, Dierich MP | title = Mechanism of human immunodeficiency virus-induced complement expression in astrocytes and neurons | journal = Journal of Virology | volume = 76 | issue = 7 | pages = 3179–88 | date = Apr 2002 | pmid = 11884542 | pmc = 136041 | doi = 10.1128/JVI.76.7.3179-3188.2002 }}
*{{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
* {{cite journal | vauthors = Ludwig MG, Seuwen K | title = Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms | journal = Journal of Receptor and Signal Transduction Research | volume = 22 | issue = 1-4 | pages = 79–110 | year = 2003 | pmid = 12503609 | doi = 10.1081/RRS-120014589 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Kimura K, Wakamatsu A, Suzuki Y, ''et al.'' |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55-65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 }}
}}
{{refend}}
{{refend}}


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[[Category:EC 4.6.1]]

Latest revision as of 22:24, 23 March 2018

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Orthologs
SpeciesHumanMouse
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Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene.[1][2] It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains.[3] ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.[3]

Structure

Structurally, ADCY2 are transmembrane proteins with twelve transmembrane segments. The protein is organized with six transmembrane segments followed by the C1 cytoplasmic domain. Then another six membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site.

This structure displays significant homology with human brain adenylyl cyclase 1(HBA C1 or ADCY1) in the highly conserved adenylyl cyclases domain found in the 3’ cytoplasmic domain of all mammalian adenylyl cyclases. Outside this domain homology is not similar suggesting that this corresponding mRNA originates from a different gene. In situ hybridization confirms a heterogeneous population of adenylyl cyclase mRNAs is expressed in the brain.[4]

Function

This gene encodes a member of the family of adenylyl cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP) from ATP. ADCY2 has also been found to accelerate phosphor-acidification, along with glycogen synthesis and breakdown.[5] This enzyme is insensitive to Ca2+/calmodulin, and is stimulated by the G protein beta and gamma subunit complex.[2] Therefore, ADCY2 is highly regulated by G-proteins, calcium, calmodulin, pyrophosphate, and post-translational modifications.

Recently, it has been discover that ADCY2 can activated by a Raf kinase-mediated serine phosphorylation.[6] In aggregate, Raf kinase associates with adenylyl cyclases and is isoform-selective, which includes adenylyl cyclase type 2. In human embryonic kidney cells, ADCY2 is stimulated by activation of Gq-coupled muscarinic receptors through protein kinase C (PKC) to generate localized cAMP. Once the agonist binding to the Gq-coupled muscarinic receptor, A-kinase-anchoring protein (AKAP) recruits PKC to activate ADCY2 to produce cAMP. The cAMP formed is degraded by phosphodiesterase 4 (PDE4) activated by an AKAP-anchored protein kinase A.[7]

Clinical significance

Polymorphisms of the ADCY2 gene have been associated with COPD and lung function.[8]

Perturbations in adenylyl cyclase activity have been implicated in alcohol and opioid addiction and is associated with human diseases, including thyroid adenoma, Anthrax, precocious puberty in males and chondrodysplasia punctata diseases.[9] During these diseases, ADCY2 undergoes a super-related pathway where protein kinase A (PKA) activation occurs in glucagon signaling and IP3 signaling. This enzyme may play a role in bipolar disorder along with other brain-expressed genes including NCALD, WDR60, SCN7A, and SPAG16.[10]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.[§ 1]

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Nicotine Activity on Dopaminergic Neurons edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".

Model organisms

Model organisms have been used in the study of ADCY2 function. A conditional knockout mouse line called Adcy2tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[11] Male and female animals underwent a standardized phenotypic screen[12] to determine the effects of deletion.[13][14][15][16] Additional screens performed: - In-depth immunological phenotyping[17] - in-depth bone and cartilage phenotyping[18]

References

  1. ↑ Stengel D, Parma J, Gannagé MH, Roeckel N, Mattei MG, Barouki R, Hanoune J (Dec 1992). "Different chromosomal localization of two adenylyl cyclase genes expressed in human brain". Human Genetics. 90 (1–2): 126–30. doi:10.1007/BF00210755. PMID 1427768.
  2. ↑ 2.0 2.1 "Entrez Gene: ADCY2 adenylyl cyclase 2 (brain)".
  3. ↑ 3.0 3.1 "Adenylate cyclase type 2". UniProt Consortium. Retrieved 28 May 2014.
  4. ↑ Stengel D, Parma J, Gannagé MH, Roeckel N, Mattei MG, Barouki R, Hanoune J (Sep–Oct 1992). "Different chromosomal localization of two adenylyl cyclase genes expressed in human brain". Human Genetics. 90 (1–2): 126–30. doi:10.1007/BF00210755. PMID 1427768.
  5. ↑ Li YX, Jin HG, Yan CG, Ren CY, Jiang CJ, Jin CD, Seo KS, Jin X (Jun 2014). "Molecular cloning, sequence identification, and gene expression analysis of bovine ADCY2 gene". Molecular Biology Reports. 41 (6): 3561–8. doi:10.1007/s11033-014-3167-9. PMID 24797538.
  6. ↑ Ding Q, Gros R, Gray ID, Taussig R, Ferguson SS, Feldman RD (Oct 2004). "Raf kinase activation of adenylyl cyclases: isoform-selective regulation". Molecular Pharmacology. 66 (4): 921–8. doi:10.1124/mol.66.4.921. PMID 15385642.
  7. ↑ Shen JX, Cooper DM (Oct 2013). "AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex". The Biochemical Journal. 455 (1): 47–56. doi:10.1042/BJ20130359. PMC 3968274. PMID 23889134.
  8. ↑ "Testing GWAS SNPs for COPD and lung function in a Polish cohort with severe COPD". Archived from the original on 2014-05-29. Retrieved 2012-12-30.
  9. ↑ "Adenylate Cyclase 2 (Brain)". Weizmann Institute of Science. Retrieved 28 May 2014.
  10. ↑ Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, Parikh SV, De Luca V, Tozzi F, Muglia P, Forte J, McQuillin A, Hu P, Gurling HM, Kennedy JL, McGuffin P, Farmer A, Strauss J, Vincent JB (2014). "Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1". BMC Medical Genetics. 15: 2. doi:10.1186/1471-2350-15-2. PMC 3901032. PMID 24387768.
  11. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  12. ↑ 12.0 12.1 "International Mouse Phenotyping Consortium".
  13. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  14. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  15. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  16. ↑ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
  17. ↑ 17.0 17.1 "Infection and Immunity Immunophenotyping (3i) Consortium".
  18. ↑ "OBCD Consortium".


External links

Further reading

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