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
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] 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] 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

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

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