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]
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.[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 discover 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]
- 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]
| Characteristic | Phenotype |
|---|---|
| All data available at.[16][21] | |
| Insulin | Normal |
| Homozygous viability at P14 | Normal |
| Homozygous Fertility | Normal |
| Body weight | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Dysmorphology | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology 16 Weeks | Normal |
| Peripheral blood leukocytes 16 Weeks | Normal |
| Heart weight | Normal |
| Salmonella infection | Normal |
| Spleen Immunophenotyping | Normal |
| Mesenteric Lymph Node Immunophenotyping | Normal |
| Epidermal Immune Composition | Normal |
References
- GRCh38: Ensembl release 89: ENSG00000078295 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000021536 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 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.
- "Entrez Gene: ADCY2 adenylyl cyclase 2 (brain)".
- "Adenylate cyclase type 2". UniProt Consortium. Retrieved 28 May 2014.
- 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.
- 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.
- 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.
- 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.
- "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.
- "Adenylate Cyclase 2 (Brain)". Weizmann Institute of Science. Retrieved 28 May 2014.
- 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.
- 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.
- "International Mouse Phenotyping Consortium".
- 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.
- Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- 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.
- 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.
- "Infection and Immunity Immunophenotyping (3i) Consortium".
- "OBCD Consortium".
External links
- Human ADCY2 genome location and ADCY2 gene details page in the UCSC Genome Browser.
Further reading
- Gaudin C, Homcy CJ, Ishikawa Y (Nov 1994). "Mammalian adenylyl cyclase family members are randomly located on different chromosomes". Human Genetics. 94 (5): 527–9. doi:10.1007/BF00211020. PMID 7959689. S2CID 40521157.
- Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
- Whisnant RE, Gilman AG, Dessauer CW (Jun 1996). "Interaction of the two cytosolic domains of mammalian adenylyl cyclase". Proceedings of the National Academy of Sciences of the United States of America. 93 (13): 6621–5. Bibcode:1996PNAS...93.6621W. doi:10.1073/pnas.93.13.6621. PMC 39075. PMID 8692867.
- Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
- Sunahara RK, Dessauer CW, Whisnant RE, Kleuss C, Gilman AG (Aug 1997). "Interaction of Gsalpha with the cytosolic domains of mammalian adenylyl cyclase". The Journal of Biological Chemistry. 272 (35): 22265–71. doi:10.1074/jbc.272.35.22265. PMID 9268375.
- Barcova M, Speth C, Kacani L, Uberall F, Stoiber H, Dierich MP (Mar 1999). "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". Pflügers Archiv. 437 (4): 538–46. doi:10.1007/s004240050815. PMID 10089566. S2CID 7620262.
- Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Jun 1999). "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". DNA Research. 6 (3): 197–205. doi:10.1093/dnares/6.3.197. PMID 10470851.
- Speth C, Joebstl B, Barcova M, Dierich MP (Apr 2000). "HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones". AIDS. 14 (6): 629–36. doi:10.1097/00002030-200004140-00001. PMID 10807185. S2CID 22105709.
- Patke CL, Shearer WT (May 2000). "gp120- and TNF-alpha-induced modulation of human B cell function: proliferation, cyclic AMP generation, Ig production, and B-cell receptor expression". The Journal of Allergy and Clinical Immunology. 105 (5): 975–82. doi:10.1067/mai.2000.105315. PMID 10808179.
- Patrizio M, Colucci M, Levi G (Apr 2001). "Human immunodeficiency virus type 1 Tat protein decreases cyclic AMP synthesis in rat microglia cultures". Journal of Neurochemistry. 77 (2): 399–407. doi:10.1046/j.1471-4159.2001.00249.x. PMID 11299302. S2CID 24053412.
- Côté M, Guillon G, Payet MD, Gallo-Payet N (Sep 2001). "Expression and regulation of adenylyl cyclase isoforms in the human adrenal gland". The Journal of Clinical Endocrinology and Metabolism. 86 (9): 4495–503. doi:10.1210/jc.86.9.4495. PMID 11549699.
- Speth C, Schabetsberger T, Mohsenipour I, Stöckl G, Würzner R, Stoiber H, Lass-Flörl C, Dierich MP (Apr 2002). "Mechanism of human immunodeficiency virus-induced complement expression in astrocytes and neurons". Journal of Virology. 76 (7): 3179–88. doi:10.1128/JVI.76.7.3179-3188.2002. PMC 136041. PMID 11884542.
- Ludwig MG, Seuwen K (2003). "Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms". Journal of Receptor and Signal Transduction Research. 22 (1–4): 79–110. doi:10.1081/RRS-120014589. PMID 12503609. S2CID 36697419.
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