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ADCY2
Identifiers
Aliases	ADCY2, AC2, HBAC2, adenylate cyclase 2 (brain), adenylate cyclase 2
External IDs	OMIM: 103071; MGI: 99676; HomoloGene: 75133; GeneCards: ADCY2; OMA:ADCY2 - orthologs
Gene location (Human)
Chr.	Chromosome 5 (human)
End	7,830,081 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	69,147,660 bp
RNA expression pattern
	Top expressed in
	middle temporal gyrus; ; Brodmann area 23; ; dorsal motor nucleus of vagus nerve; ; Skeletal muscle tissue of rectus abdominis; ; entorhinal cortex; ; postcentral gyrus; ; muscle of thigh; ; biceps brachii; ; deltoid muscle; ; Skeletal muscle tissue of biceps brachii;
	Top expressed in
	primary motor cortex; ; CA3 field; ; cingulate gyrus; ; digastric muscle; ; Region I of hippocampus proper; ; primary visual cortex; ; temporal muscle; ; superior frontal gyrus; ; extraocular muscle; ; sternocleidomastoid muscle;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	nucleotide binding; manganese ion binding; adenylate cyclase binding; metal ion binding; lyase activity; protein heterodimerization activity; phosphorus-oxygen lyase activity; ATP binding; magnesium ion binding; guanylate cyclase activity; adenylate cyclase activity;
Cellular component	cytoplasm; integral component of membrane; membrane; plasma membrane; integral component of plasma membrane; intracellular anatomical structure; dendrite; membrane raft; guanylate cyclase complex, soluble;
Biological process	intracellular signal transduction; cellular response to forskolin; adenylate cyclase-modulating G protein-coupled receptor signaling pathway; cellular response to glucagon stimulus; cyclic nucleotide biosynthetic process; renal water homeostasis; cAMP biosynthetic process; cGMP biosynthetic process; signal transduction; adenylate cyclase-activating G protein-coupled receptor signaling pathway; adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; cAMP-mediated signaling; G protein-coupled receptor signaling pathway; activation of adenylate cyclase activity; activation of protein kinase A activity;
	Sources:Amigo / QuickGO
Orthologs
	108
	210044
	ENSG00000078295
	ENSMUSG00000021536
	Q08462
	Q80TL1; Q3V1Q3
	NM_020546
	NM_153534
	NP_065433
	NP_705762
	Wikidata
View/Edit Human	View/Edit Mouse

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 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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|alt=Nicotine Activity on Dopaminergic Neurons edit]]

Nicotine Activity on Dopaminergic Neurons edit

^ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000078295 – Ensembl, May 2017
^ ^a ^b ^c 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.
^ ^a ^b "Entrez Gene: ADCY2 adenylyl cyclase 2 (brain)".
^ ^a ^b "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.