P97490 · ADCY8_MOUSE

  • Protein
    Adenylate cyclase type 8
  • Gene
    Adcy8
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion (PubMed:10482244, PubMed:10864938, PubMed:14585998, PubMed:18448650, PubMed:25403481).
Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation (PubMed:10482244, PubMed:10864938, PubMed:12441059, PubMed:14585998, PubMed:18222416, PubMed:18448650, PubMed:20638449, PubMed:27234425).
Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment (PubMed:25403481).
Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells (By similarity).

Catalytic activity

Cofactor

Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Mn2+ (UniProtKB | Rhea| CHEBI:29035 )

Note: Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).

Activity regulation

At rest, the N- and C-terminal domains interact, as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain. Upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain. Fully calcium-saturated calmodulin then leaves the N-terminal domain, binding solely to the C-terminal domain, and the whole autoinhibitory complex dissociates, resulting in activation of adenylate cyclase. As local calcium concentrations decrease, the calmodulin becomes calcium free and binds once more to the N-terminal domain, whereupon the whole system returns to rest with the re-association of the autoinhibitory complex (PubMed:14585998).
In non-excitable cells, activated by capacitative calcium entry (CCE) through store-operated channels, namely through interaction with ORAI1 and STIM1; membrane raft and caveolae localization and membrane integrity are indispensable. CCE-mediated adenylate cyclase activity is decreased by AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-regulated by AKAP9 and the mitochondrially targeted AKAP1. In excitable cells, activated during membrane depolarization through L-type voltage-gated calcium channels (VGCC), leading to calcium entry; the L-type alpha subunit is sufficient. Activated via stimulation of the GLP1R. Synergistically activated by calcium/calmodulin and GNAS. Stimulated by forskolin. Inhibited by PKA directly bound to AKAP5 at membrane raft. Inhibition by acute activation of OPRM1 and activation by chronic activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by G beta-gamma dimer (By similarity).

Features

Showing features for binding site, site.

TypeIDPosition(s)Description
Binding site417Mg2+ 1 (UniProtKB | ChEBI); catalytic
Binding site417Mg2+ 2 (UniProtKB | ChEBI); catalytic
Binding site417-422ATP (UniProtKB | ChEBI)
Binding site418Mg2+ 2 (UniProtKB | ChEBI); catalytic
Binding site459-461ATP (UniProtKB | ChEBI)
Binding site461Mg2+ 1 (UniProtKB | ChEBI); catalytic
Binding site461Mg2+ 2 (UniProtKB | ChEBI); catalytic
Binding site505ATP (UniProtKB | ChEBI)
Binding site1032ATP (UniProtKB | ChEBI)
Binding site1107-1109ATP (UniProtKB | ChEBI)
Binding site1114-1118ATP (UniProtKB | ChEBI)
Binding site1154ATP (UniProtKB | ChEBI)
Site1197Essential for autoinhibition maintenance by promoting interaction of the N and C termini
Site1198Essential for autoinhibition maintenance
Site1201Essential for autoinhibition maintenance by promoting interaction of the N and C termini
Site1203Essential for CALM1 interaction
Site1205Essential for CALM1 interaction

GO annotations

AspectTerm
Cellular Componentapical plasma membrane
Cellular Componentaxon
Cellular Componentbasolateral plasma membrane
Cellular Componentcaveola
Cellular Componentclathrin-coated pit
Cellular Componentclathrin-coated vesicle membrane
Cellular Componentdendrite
Cellular Componentexcitatory synapse
Cellular Componentglutamatergic synapse
Cellular Componenthippocampal mossy fiber to CA3 synapse
Cellular Componentmembrane raft
Cellular Componentneuronal cell body membrane
Cellular Componentplasma membrane
Cellular Componentplasma membrane raft
Cellular Componentpostsynaptic density
Cellular Componentpresynaptic active zone
Cellular Componentpresynaptic membrane
Cellular ComponentSchaffer collateral - CA1 synapse
Molecular Functionactin binding
Molecular Functionadenylate cyclase activity
Molecular FunctionATP binding
Molecular Functioncalcium- and calmodulin-responsive adenylate cyclase activity
Molecular Functioncalmodulin binding
Molecular Functionmetal ion binding
Molecular Functionphosphatase binding
Molecular Functionprotein dimerization activity
Molecular Functionprotein heterodimerization activity
Molecular Functionprotein homodimerization activity
Molecular Functionprotein phosphatase 2A binding
Biological Processactivation of protein kinase A activity
Biological Processadenylate cyclase-activating G protein-coupled receptor signaling pathway
Biological ProcesscAMP biosynthetic process
Biological ProcesscAMP-mediated signaling
Biological Processcellular response to calcium ion
Biological Processcellular response to forskolin
Biological Processcellular response to glucagon stimulus
Biological Processcellular response to glucose stimulus
Biological Processcellular response to morphine
Biological ProcessG protein-coupled opioid receptor signaling pathway
Biological Processglucose homeostasis
Biological Processglucose mediated signaling pathway
Biological Processlocomotory behavior
Biological Processlong-term memory
Biological Processmemory
Biological Processmodulation of chemical synaptic transmission
Biological Processneuroinflammatory response
Biological Processpositive regulation of CREB transcription factor activity
Biological Processpositive regulation of cytosolic calcium ion concentration
Biological Processpositive regulation of insulin secretion
Biological Processpositive regulation of insulin secretion involved in cellular response to glucose stimulus
Biological Processpositive regulation of long-term synaptic depression
Biological Processpositive regulation of long-term synaptic potentiation
Biological Processpositive regulation of synaptic plasticity
Biological Processprotein complex oligomerization
Biological Processprotein homooligomerization
Biological Processregulation of cellular response to stress
Biological Processregulation of cytosolic calcium ion concentration

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Adenylate cyclase type 8
  • EC number
  • Alternative names
    • ATP pyrophosphate-lyase 8
    • Adenylate cyclase type VIII
    • Adenylyl cyclase 8
    • Ca(2+)/calmodulin-activated adenylyl cyclase

Gene names

    • Name
      Adcy8

Organism names

  • Taxonomic identifier
  • Strains
    • BALB/cJ
    • C57BL/6J
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    P97490
  • Secondary accessions
    • G3X8V9

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Multi-pass membrane protein
Apical cell membrane
Synapse
Cell projection, axon
Postsynaptic density
Membrane raft
Membrane, coated pit
Membrane, caveola
Note: Localized to dendritic arbors (PubMed:17335981).
Monomeric N-glycosylated species localizes in membrane raft. In contrast, monomeric unglycosylated forms are enriched in clathrin-coated pits and vesicles. Dimers are also localized outside of membrane rafts. Membrane raft localization and integrity is indispensable for CCE-stimulated adenylate cyclase activity (By similarity).

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain1-180Cytoplasmic
Transmembrane181-201Helical
Transmembrane210-230Helical
Transmembrane245-265Helical
Transmembrane272-292Helical
Transmembrane294-314Helical
Transmembrane319-339Helical
Topological domain340-713Cytoplasmic
Transmembrane714-734Helical
Transmembrane736-756Helical
Transmembrane785-805Helical
Transmembrane829-849Helical
Transmembrane859-879Helical
Transmembrane892-912Helical
Topological domain913-1249Cytoplasmic

Keywords

Phenotypes & Variants

Disruption phenotype

Adcy8 knockout mice are fertile and seem normal. However mice reveal a tendency for both male and female to be somewhat smaller from day of life 45 and 30 respectively while food intake is normal. From there, females remain 10-15% smaller. In contrast, male transiently grew more slowly between day of life 45 and 92, after which point differences are not significant. Mice are less nervous.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 55 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

PTM/Processing

Features

Showing features for chain, modified residue, glycosylation.

TypeIDPosition(s)Description
ChainPRO_00001957061-1249Adenylate cyclase type 8
Modified residue55Omega-N-methylarginine
Modified residue612Phosphoserine
Modified residue622Phosphoserine
Glycosylation815N-linked (GlcNAc...) asparagine
Glycosylation819N-linked (GlcNAc...) asparagine
Glycosylation886N-linked (GlcNAc...) asparagine

Post-translational modification

Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8.
N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Abundantly expressed within the olfactory bulb, thalamus, habenula, CA1 region of the hippocampus, and hypothalamus (PubMed:10864938).
Strongly expressed in pyramidal cells of CA1 and weakly in CA3 and the dentate gyrus. Strongly and homogeneously expressed in all cell layers of the anterior cingulate cortex (ACC). Widely expressed in the insular cortex. Weakly expressed in the spinal dorsal horn (PubMed:12441059).
Abundantly present in the CA1/CA2 region in the hippocampus neonatal and intensifies by adulthood. Weakly expressed in the cerebellum at postnatal day 7 and decreased further by postnatal day 14 (PubMed:17335981).

Gene expression databases

Interaction

Subunit

Homodimer; via transmembrane domain (PubMed:19158400).
Monomer (PubMed:19158400).
Heterodimer. Oligemer; via transmembrane domain. Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity through PKA phosphorylation. Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory effects of PKA on adenylate cyclase activity; interaction is dependent of catalytically active PPP2CA; antagonizes interaction with calmodulin. Interacts with AKAP5 (palmitoylated form); promotes the phosphorylation of ADCY8 after store-operated calcium entry (SOCE) stimulation at membrane raft. Interacts with ORAI1; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events. Interacts with STIM1. Interacts with actin; interaction is calcium independent; interaction is affected by calcium-calmodulin; interaction controls the distribution and regulation of ADCY8. Interacts with calmodulin; at rest, interacts via N-terminal domain; upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain forming an autoinhibitory complex; fully calcium-saturated calmodulin leaves the N-terminal domain, binding solely to the C-terminal domain leading to dissociation of autoinhibitory complex and resulting in activation of adenylate cyclase; antagonizes interaction with PPP2CA; interaction is calcium dependent. Interacts with PPP2R5D (By similarity).

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for region, motif, compositional bias.

TypeIDPosition(s)Description
Region1-107Involved in AKAP5 and PRKAR2A interaction
Region1-180Involved in ORAI1, STIM1, PPP2CA and PPP2R1A interaction
Region14-33Disordered
Motif38-40Essential for CALM1 interaction
Motif49-51Essential for CALM1 interaction
Region50-118Disordered
Compositional bias68-87Polar residues
Region1107-1249Involved in CALM1 interaction
Region1198-1213Required for both calcium stimulation and maintenance of autoinhibition
Region1221-1249Disordered

Domain

The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain. The two transmembrane clusters are necessary and suficient for the plasma membrane targeting and oligomers assembly. The N-terminal and C-terminal domains interact at rest as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain; the binding is specifically inhibited by fully calcium-saturated calmodulin, resulting in activation of AC8.

Sequence similarities

Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    1,249
  • Mass (Da)
    140,095
  • Last updated
    2012-10-03 v2
  • Checksum
    26103B6E0DB9C701
MELSDVHCLSGSEELYTIQPTPPAGDDGSGSRPQRLLWQTAVRHITEQRFIHGHRGGGGGGVSRKASNPAGSGPNHHAPQLSSDSVLPLYSLGPGERAHNTGGTKVFPERSGSGSASGSGGGGDLGFLHLDCAPSNSDFFLNGGYSYRGVIFPTLRNSFKSRDLERLYQRYFLGQRRKSEVVMNVLDVLTKLTLLVLHLSLASAPMDPLKGILLGFFTGIEVVICALVVVRKDNTSHTYLQYSGVVTWVAMTTQILAAGLGYGLLGDGIGYVLFTLFATYSMLPLPLTWAILAGLGTSLLQVTLQVLIPRLAVFSINQVLAQVVLFMCMNTAGIFISYLSDRAQRQAFLETRRCVEARLRLETENQRQERLVLSVLPRFVVLEMINDMTNVEDEHLQHQFHRIYIHRYENVSILFADVKGFTNLSTTLSAQELVRMLNELFARFDRLAHEHHCLRIKILGDCYYCVSGLPEPRRDHAHCCVEMGLSMIKTIRFVRSRTKHDVDMRIGIHSGSVLCGVLGLRKWQFDVWSWDVDIANKLESGGIPGRIHISKATLDCLNGDYNVEEGHGKERNEFLRKHNIETYLIKQPEESLLCLPEDIVKESVSCSDRRNSGATFTEGSWSPELPFDNIVGKQNTLAALTRNSINLLPNHLAQALHVQSGPEEINKRIEHTIDLRSGDKLRREHIKPFSLMFKDSSLEHKYSQMRDEVFKSNLVCAFIVLLFITAIQSLLPSSRLMPMTIQFSILIMLHSALVLITTAEDYKCLPLILRKTCCWINETYLARNVIIFASILINFLGAVLNILWCDFDKSIPLKNLTFNSSAVFTDICSYPEYFVFTGVLAMVTCAVFLRLNSVLKLAVLLIMIAIYALLTETIYAGLFLSYDNLNHSGEDFLGTKEASLLLMAMFLLAVFYHGQQLEYTARLDFLWRVQAKEEINEMKELREHNENMLRNILPSHVARHFLEKDRDNEELYSQSYDAVGVMFASIPGFADFYSQTEMNNQGVECLRLLNEIIADFDELLGEDRFQDIEKIKTIGSTYMAVSGLSPEKQQCEDKWGHLCALADFSLALTESIQEINKHSFNNFELRIGISHGSVVAGVIGAKKPQYDIWGKTVNLASRMDSTGVSGRIQVPEETYLILKDQGFAFDYRGEIYVKGISEQEGKIKTYFLLGRVQPNPFILPPRRLPGQYSLAAVVLGLVQSLNRQRQKQLLNENSNSGIIKSHYNRRTLLTPSGPEPGAQAEGTDKSDLP

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
A0A2I3BQ46A0A2I3BQ46_MOUSEAdcy81219

Features

Showing features for sequence conflict, compositional bias.

TypeIDPosition(s)Description
Sequence conflict24in Ref. 1; AAB41885
Sequence conflict59in Ref. 1; AAB41885
Compositional bias68-87Polar residues
Sequence conflict849in Ref. 1; AAB41885

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
U85021
EMBL· GenBank· DDBJ
AAB41885.1
EMBL· GenBank· DDBJ
mRNA
AC116996
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
AC160934
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
CH466545
EMBL· GenBank· DDBJ
EDL29360.1
EMBL· GenBank· DDBJ
Genomic DNA
CH466545
EMBL· GenBank· DDBJ
EDL29361.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.
FeedbackHelp