ADCY2

Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene.[5][6] It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains.[7] 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.[7]

ADCY2
Identifiers
AliasesADCY2, AC2, HBAC2, adenylate cyclase 2 (brain), adenylate cyclase 2
External IDsOMIM: 103071 MGI: 99676 HomoloGene: 75133 GeneCards: ADCY2
Orthologs
SpeciesHumanMouse
Entrez

108

210044

Ensembl

ENSG00000078295

ENSMUSG00000021536

UniProt

Q08462

Q80TL1
Q3V1Q3

RefSeq (mRNA)

NM_020546

NM_153534

RefSeq (protein)

NP_065433

NP_705762

Location (UCSC)Chr 5: 7.4 – 7.83 MbChr 13: 68.77 – 69.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 which is 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.[8]

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.[9] This enzyme is insensitive to Ca2+/calmodulin, and is stimulated by the G protein beta and gamma subunit complex.[6] Therefore, ADCY2 is highly regulated by G-proteins, calcium, calmodulin, pyrophosphate, and post-translational modifications.

Recently, it has been discovered that ADCY2 can activated by a Raf kinase-mediated serine phosphorylation.[10] 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.[11]

Clinical significance

Polymorphisms of the ADCY2 gene have been associated with COPD and lung function.[12]

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.[13] 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.[14]

Interactive pathway map

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

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NicotineDopaminergic_WP1602
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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.[15] Male and female animals underwent a standardized phenotypic screen[16] to determine the effects of deletion.[17][18][19][20] Additional screens performed: - In-depth immunological phenotyping[21] - in-depth bone and cartilage phenotyping[22]

References

  1. GRCh38: Ensembl release 89: ENSG00000078295 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000021536 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. S2CID 1740589.
  6. "Entrez Gene: ADCY2 adenylyl cyclase 2 (brain)".
  7. "Adenylate cyclase type 2". UniProt Consortium. Retrieved 28 May 2014.
  8. 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. S2CID 1740589.
  9. 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. S2CID 15707529.
  10. 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.
  11. 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.
  12. "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.
  13. "Adenylate Cyclase 2 (Brain)". Weizmann Institute of Science. Retrieved 28 May 2014.
  14. 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.
  15. 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. S2CID 85911512.
  16. "International Mouse Phenotyping Consortium".
  17. 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.
  18. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  19. 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. S2CID 18872015.
  20. 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.
  21. "Infection and Immunity Immunophenotyping (3i) Consortium".
  22. "OBCD Consortium".

Further reading

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