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ADCY2

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Identifiers
SymbolsADCY2 ; AC2; HBAC2
External IDsOMIM103071 MGI99676 HomoloGene75133 IUPHAR: 1279 ChEMBL: 3760 GeneCards: ADCY2 Gene
EC number4.6.1.1
RNA expression pattern
File:PBB GE ADCY2 213217 at tn.png
File:PBB GE ADCY2 213219 at tn.png
File:PBB GE ADCY2 217687 at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez108210044
EnsemblENSG00000078295ENSMUSG00000021536
UniProtQ08462Q3V1Q3
RefSeq (mRNA)NM_020546NM_153534
RefSeq (protein)NP_065433NP_705762
Location (UCSC)Chr 5:
7.4 – 7.83 Mb
Chr 13:
68.62 – 69 Mb
PubMed search[1][2]

Adenylate 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 adenylate 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 adenylate 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 et al. (Dec 1992). "Different chromosomal localization of two adenylyl cyclase genes expressed in human brain". Human Genetics 90 (1–2): 126–30. PMID 1427768. doi:10.1007/BF00210755. 
  2. ^ a b "Entrez Gene: ADCY2 adenylate cyclase 2 (brain)". 
  3. ^ a b "Adenylate cyclase type 2". UniProt Consortium. Retrieved 28 May 2014. 
  4. ^ Stengel D, Parma J, Gannagé MH, Roeckel N, Mattei MG, Barouki R et al. (Sep–Oct 1992). "Different chromosomal localization of two adenylyl cyclase genes expressed in human brain". Human Genetics 90 (1–2): 126–30. PMID 1427768. doi:10.1007/BF00210755. 
  5. ^ Li YX, Jin HG, Yan CG, Ren CY, Jiang CJ, Jin CD et al. (Jun 2014). "Molecular cloning, sequence identification, and gene expression analysis of bovine ADCY2 gene". Molecular Biology Reports 41 (6): 3561–8. PMID 24797538. doi:10.1007/s11033-014-3167-9. 
  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. PMID 15385642. doi:10.1124/mol.66.4. 
  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. PMC 3968274. PMID 23889134. doi:10.1042/BJ20130359. 
  8. ^ "Testing GWAS SNPs for COPD and lung function in a Polish cohort with severe COPD". 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 et al. (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. PMC 3901032. PMID 24387768. doi:10.1186/1471-2350-15-2. 
  11. ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Opthalmologica 88: 925-7.doi:10.1111/j.1755-3768.2010.4142.x: Wiley. 
  12. ^ a b "International Mouse Phenotyping Consortium". 
  13. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V et al. (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337â€"42. PMC 3572410. PMID 21677750. doi:10.1038/nature10163. 
  14. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. PMID 21677718. doi:10.1038/474262a. 
  15. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9â€"13. PMID 17218247. doi:10.1016/j.cell.2006.12.018. 
  16. ^ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN et al. (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. PMID 23870131. doi:10.1016/j.cell.2013.06.022. 
  17. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium". 
  18. ^ a b "OBCD Consortium". 

Further reading

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