ADCY2

Protein-coding gene in the species Homo sapiens

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)^[1]

Band	5p15.31	Start	7,396,138 bp^[1]
Band	5p15.31	End	7,830,081 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 13 (mouse)^[2]

Band	13 B3\|13 35.55 cM	Start	68,768,162 bp^[2]
Band	13 B3\|13 35.55 cM	End	69,147,660 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

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

BioGPS


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

Species

Human

Mouse

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 Mb

Chr 13: 68.77 – 69.15 Mb

PubMed search

^[3]

^[4]

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]}

[[File:

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

|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.

External links

Human ADCY2 genome location and ADCY2 gene details page in the UCSC Genome Browser.

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/jcem.86.9.7837. 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.

PDB gallery

1ab8: RAT TYPE II ADENYLYL CYCLASE C2 DOMAIN/FORSKOLIN COMPLEX
1azs: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE
1cjk: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH ADENOSINE 5'-(ALPHA THIO)-TRIPHOSPHATE (RP), MG, AND MN
1cjt: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH BETA-L-2',3'-DIDEOXYATP, MN, AND MG
1cju: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH BETA-L-2',3'-DIDEOXYATP AND MG
1cjv: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH BETA-L-2',3'-DIDEOXYATP, MG, AND ZN
1cs4: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH 2'-DEOXY-ADENOSINE 3'-MONOPHOSPHATE, PYROPHOSPHATE AND MG
1cul: COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH 2',5'-DIDEOXY-ADENOSINE 3'-TRIPHOSPHATE AND MG
1tl7: Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With 2'(3')-O-(N-methylanthraniloyl)-guanosine 5'-triphosphate and Mn
1u0h: STRUCTURAL BASIS FOR THE INHIBITION OF MAMMALIAN ADENYLYL CYCLASE BY MANT-GTP
2gvd: Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn
2gvz: Crystal Structure of Complex of Gs- with The Catalytic Domains of Mammalian Adenylyl Cyclase: Complex with MANT-ATP and Mn

Phosphorus–oxygen lyases (EC 4.6)

4.6.1

Adenylate cyclase
(4.6.1.1)

intracellular	ADCY1 ADCY2 ADCY3 ADCY4 ADCY5 ADCY6 ADCY7 ADCY8 ADCY9 ADCY10
extracellular	Extracellular adenylate cyclase

Guanylate cyclase
(4.6.1.2)

soluble guanylyl cyclase	GUCY1A2 GUCY1A3 GUCY1B2 GUCY1B3
guanylate cyclase-coupled receptor	GUCY2C GUCY2D ANP (NPR1 NPR2)

Other

Cytidylate cyclase
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase
Phosphatidylinositol diacylglycerol-lyase
Glycosylphosphatidylinositol diacylglycerol-lyase
FAD-AMP lyase (cyclizing)

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)