ADCY2

Last updated
ADCY2
Protein ADCY2 PDB 1ab8.png
Identifiers
Aliases ADCY2 , AC2, HBAC2, adenylate cyclase 2 (brain), adenylate cyclase 2
External IDs OMIM: 103071 MGI: 99676 HomoloGene: 75133 GeneCards: ADCY2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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]

Contents

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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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. [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]

Related Research Articles

<span class="mw-page-title-main">Adenylyl cyclase</span> Enzyme with key regulatory roles in most cells

Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:

<span class="mw-page-title-main">Cyclic adenosine monophosphate</span> Cellular second messenger

Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">GNAS complex locus</span> Gene locus

GNAS complex locus is a gene locus in humans. Its main product is the heterotrimeric G-protein alpha subunit Gs, a key component of G protein-coupled receptor-regulated adenylyl cyclase signal transduction pathways. GNAS stands for Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide.

<span class="mw-page-title-main">Pituitary adenylate cyclase-activating peptide</span> Protein-coding gene in the species Homo sapiens

Pituitary adenylate cyclase-activating polypeptide also known as PACAP is a protein that in humans is encoded by the ADCYAP1 gene. pituitary adenylate cyclase-activating polypeptide is similar to vasoactive intestinal peptide. One of its effects is to stimulate enterochromaffin-like cells. It binds to vasoactive intestinal peptide receptor and to the pituitary adenylate cyclase-activating polypeptide receptor.

<span class="mw-page-title-main">Heterotrimeric G protein</span> Class of enzymes

Heterotrimeric G protein, also sometimes referred to as the "large" G proteins are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors, directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.

G<sub>s</sub> alpha subunit Mammalian protein found in Homo sapiens

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

<span class="mw-page-title-main">CAMK2G</span> Protein-coding gene in the species Homo sapiens

Calcium/calmodulin-dependent protein kinase type II gamma chain is an enzyme that in humans is encoded by the CAMK2G gene.

<span class="mw-page-title-main">PRKAB1</span> Protein-coding gene in the species Homo sapiens

5'-AMP-activated protein kinase subunit beta-1 is an enzyme that in humans is encoded by the PRKAB1 gene.

<span class="mw-page-title-main">ADCY6</span> Protein-coding gene in humans

Adenylyl cyclase type 6 is an enzyme that in humans is encoded by the ADCY6 gene.

<span class="mw-page-title-main">ADCY3</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 3 is an enzyme that in humans is encoded by the ADCY3 gene.

<span class="mw-page-title-main">ADCY5</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.

<span class="mw-page-title-main">ADCY1</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 1 is an enzyme that in humans is encoded by the ADCY1 gene.

<span class="mw-page-title-main">ADCY7</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 7 is an enzyme that in humans is encoded by the ADCY7 gene.

<span class="mw-page-title-main">ADCY9</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 9 is an enzyme that in humans is encoded by the ADCY9 gene.

<span class="mw-page-title-main">ADCY8</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 8 is an enzyme that in humans is encoded by the ADCY8 gene.

<span class="mw-page-title-main">ADCY4</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 4 is an enzyme that in humans is encoded by the ADCY4 gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

<span class="mw-page-title-main">ADCY10</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase 10 also known as ADCY10 is an enzyme that, in humans, is encoded by the ADCY10 gene.

Soluble adenylyl cyclase (sAC) is a regulatory cytosolic enzyme present in almost every cell. sAC is a source of cyclic adenosine 3’,5’ monophosphate (cAMP) – a second messenger that mediates cell growth and differentiation in organisms from bacteria to higher eukaryotes. sAC differentiates from the transmembrane adenylyl cyclase (tmACs) – an important source of cAMP; in that sAC is regulated by bicarbonate anions and it is dispersed throughout the cell cytoplasm. sAC has been found to have various functions in physiological systems different from that of the tmACs.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000078295 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021536 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. 1 2 "Entrez Gene: ADCY2 adenylyl cyclase 2 (brain)".
  7. 1 2 "Adenylate cyclase type 2". UniProt Consortium. Retrieved 28 May 2014.
  8. 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.
  9. 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.
  10. 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.
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Further reading