ID ADCY8_MOUSE Reviewed; 1249 AA.
AC P97490; G3X8V9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 2.
DT 24-JAN-2024, entry version 168.
DE RecName: Full=Adenylate cyclase type 8 {ECO:0000305};
DE EC=4.6.1.1 {ECO:0000250|UniProtKB:P40146};
DE AltName: Full=ATP pyrophosphate-lyase 8;
DE AltName: Full=Adenylate cyclase type VIII {ECO:0000250|UniProtKB:P40145};
DE AltName: Full=Adenylyl cyclase 8 {ECO:0000250|UniProtKB:P40146};
DE AltName: Full=Ca(2+)/calmodulin-activated adenylyl cyclase;
GN Name=Adcy8 {ECO:0000312|MGI:MGI:1341110};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ; TISSUE=Brain;
RA Premont R.T.;
RT "Cloning of mouse adenylyl cyclase type 8.";
RL Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION.
RX PubMed=10482244; DOI=10.1016/s0896-6273(01)80036-2;
RA Wong S.T., Athos J., Figueroa X.A., Pineda V.V., Schaefer M.L.,
RA Chavkin C.C., Muglia L.J., Storm D.R.;
RT "Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-
RT dependent long-term memory and late phase LTP.";
RL Neuron 23:787-798(1999).
RN [5]
RP TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=10864938; DOI=10.1523/jneurosci.20-13-04809.2000;
RA Schaefer M.L., Wong S.T., Wozniak D.F., Muglia L.M., Liauw J.A., Zhuo M.,
RA Nardi A., Hartman R.E., Vogt S.K., Luedke C.E., Storm D.R., Muglia L.J.;
RT "Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient
RT mice.";
RL J. Neurosci. 20:4809-4820(2000).
RN [6]
RP TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=12441059; DOI=10.1016/s0896-6273(02)01019-x;
RA Wei F., Qiu C.S., Kim S.J., Muglia L., Maas J.W., Pineda V.V., Xu H.M.,
RA Chen Z.F., Storm D.R., Muglia L.J., Zhuo M.;
RT "Genetic elimination of behavioral sensitization in mice lacking
RT calmodulin-stimulated adenylyl cyclases.";
RL Neuron 36:713-726(2002).
RN [7]
RP SUBCELLULAR LOCATION, FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=14585998; DOI=10.1523/jneurosci.23-30-09710.2003;
RA Wang H., Pineda V.V., Chan G.C., Wong S.T., Muglia L.J., Storm D.R.;
RT "Type 8 adenylyl cyclase is targeted to excitatory synapses and required
RT for mossy fiber long-term potentiation.";
RL J. Neurosci. 23:9710-9718(2003).
RN [8]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=17335981; DOI=10.1016/j.neuroscience.2007.01.045;
RA Conti A.C., Maas J.W. Jr., Muglia L.M., Dave B.A., Vogt S.K., Tran T.T.,
RA Rayhel E.J., Muglia L.J.;
RT "Distinct regional and subcellular localization of adenylyl cyclases type 1
RT and 8 in mouse brain.";
RL Neuroscience 146:713-729(2007).
RN [9]
RP FUNCTION.
RX PubMed=18222416; DOI=10.1016/j.biopsych.2007.11.021;
RA Zachariou V., Liu R., LaPlant Q., Xiao G., Renthal W., Chan G.C.,
RA Storm D.R., Aghajanian G., Nestler E.J.;
RT "Distinct roles of adenylyl cyclases 1 and 8 in opiate dependence:
RT behavioral, electrophysiological, and molecular studies.";
RL Biol. Psychiatry 63:1013-1021(2008).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18448650; DOI=10.1523/jneurosci.1177-08.2008;
RA Zhang M., Moon C., Chan G.C., Yang L., Zheng F., Conti A.C., Muglia L.,
RA Muglia L.J., Storm D.R., Wang H.;
RT "Ca-stimulated type 8 adenylyl cyclase is required for rapid acquisition of
RT novel spatial information and for working/episodic-like memory.";
RL J. Neurosci. 28:4736-4744(2008).
RN [11]
RP SUBUNIT.
RX PubMed=19158400; DOI=10.1152/ajpcell.00488.2008;
RA Pagano M., Clynes M.A., Masada N., Ciruela A., Ayling L.J., Wachten S.,
RA Cooper D.M.;
RT "Insights into the residence in lipid rafts of adenylyl cyclase AC8 and its
RT regulation by capacitative calcium entry.";
RL Am. J. Physiol. 296:C607-C619(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-612 AND SER-622, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Lung;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [13]
RP FUNCTION.
RX PubMed=20638449; DOI=10.1016/j.neuroscience.2010.07.022;
RA Razzoli M., Andreoli M., Maraia G., Di Francesco C., Arban R.;
RT "Functional role of Calcium-stimulated adenylyl cyclase 8 in adaptations to
RT psychological stressors in the mouse: implications for mood disorders.";
RL Neuroscience 170:429-440(2010).
RN [14]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-55, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [15]
RP FUNCTION.
RX PubMed=25403481; DOI=10.1007/s00125-014-3445-z;
RA Raoux M., Vacher P., Papin J., Picard A., Kostrzewa E., Devin A.,
RA Gaitan J., Limon I., Kas M.J., Magnan C., Lang J.;
RT "Multilevel control of glucose homeostasis by adenylyl cyclase 8.";
RL Diabetologia 58:749-757(2015).
RN [16]
RP FUNCTION.
RX PubMed=27234425; DOI=10.1186/s13041-016-0239-x;
RA Bernabucci M., Zhuo M.;
RT "Calcium activated adenylyl cyclase AC8 but not AC1 is required for
RT prolonged behavioral anxiety.";
RL Mol. Brain 9:60-60(2016).
CC -!- FUNCTION: Catalyzes the formation of cAMP in response to calcium entry
CC leadings to cAMP signaling activation that affect processes suche as
CC synaptic plasticity and insulin secretion (PubMed:10864938,
CC PubMed:25403481, PubMed:10482244, PubMed:14585998, PubMed:18448650).
CC Plays a role in many brain functions, such as learning, memory, drug
CC addiction, and anxiety modulation through regulation of synaptic
CC plasticity by modulating long-term memory and long-term potentiation
CC (LTP) through CREB transcription factor activity modulation
CC (PubMed:10482244, PubMed:14585998, PubMed:18448650, PubMed:10864938,
CC PubMed:12441059, PubMed:20638449, PubMed:27234425, PubMed:18222416).
CC Plays a central role in insulin secretion by controlling glucose
CC homeostasis through glucagon-like peptide 1 and glucose signaling
CC pathway and maintains insulin secretion through calcium-dependent PKA
CC activation leading to vesicle pool replenishment (PubMed:25403481).
CC Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2
CC secretion by switching from a negative to a positive regulation, during
CC the IL1B induced-dedifferentiation of smooth muscle cells (By
CC similarity). {ECO:0000250|UniProtKB:P40146,
CC ECO:0000269|PubMed:10482244, ECO:0000269|PubMed:10864938,
CC ECO:0000269|PubMed:12441059, ECO:0000269|PubMed:14585998,
CC ECO:0000269|PubMed:18222416, ECO:0000269|PubMed:18448650,
CC ECO:0000269|PubMed:20638449, ECO:0000269|PubMed:25403481,
CC ECO:0000269|PubMed:27234425}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1;
CC Evidence={ECO:0000250|UniProtKB:P40146};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P40146};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P40146};
CC Note=Binds 2 magnesium ions per subunit. Is also active with manganese
CC (in vitro). {ECO:0000250|UniProtKB:P30803};
CC -!- ACTIVITY REGULATION: At rest, the N- and C-terminal domains interact,
CC as part of a larger autoinhibitory complex, with calmodulin pre-
CC associated at the N-terminal domain. Upon a calcium rise, calmodulin
CC becomes calcium-saturated and subsequently binds to the C-terminal
CC domain. Fully calcium-saturated calmodulin then leaves the N-terminal
CC domain, binding solely to the C-terminal domain, and the whole
CC autoinhibitory complex dissociates, resulting in activation of
CC adenylate cyclase. As local calcium concentrations decrease, the
CC calmodulin becomes calcium free and binds once more to the N-terminal
CC domain, whereupon the whole system returns to rest with the re-
CC association of the autoinhibitory complex (PubMed:14585998). In non-
CC excitable cells, activated by capacitative calcium entry (CCE) through
CC store-operated channels, namely through interaction with ORAI1 and
CC STIM1; membrane raft and caveolae localization and membrane integrity
CC are indispensable. CCE-mediated adenylate cyclase activity is decreased
CC by AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-
CC regulated by AKAP9 and the mitochondrially targeted AKAP1. In excitable
CC cells, activated during membrane depolarization through L-type voltage-
CC gated calcium channels (VGCC), leading to calcium entry; the L-type
CC alpha subunit is sufficient. Activated via stimulation of the GLP1R.
CC Synergistically activated by calcium/calmodulin and GNAS. Stimulated by
CC forskolin. Inhibited by PKA directly bound to AKAP5 at membrane raft.
CC Inhibition by acute activation of OPRM1 and activation by chronic
CC activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and
CC G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by
CC G beta-gamma dimer (By similarity). {ECO:0000250|UniProtKB:P40146,
CC ECO:0000269|PubMed:14585998}.
CC -!- SUBUNIT: Homodimer; via transmembrane domain (PubMed:19158400). Monomer
CC (PubMed:19158400). Heterodimer. Oligemer; via transmembrane domain.
CC Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity
CC through PKA phosphorylation. Interacts with PPP2CA and PPP2R1A; does
CC not mediate the inhibitory effects of PKA on adenylate cyclase
CC activity; interaction is dependent of catalytically active PPP2CA;
CC antagonizes interaction with calmodulin. Interacts with AKAP5
CC (palmitoylated form); promotes the phosphorylation of ADCY8 after
CC store-operated calcium entry (SOCE) stimulation at membrane raft.
CC Interacts with ORAI1; interaction is calcium store depletion
CC independent; interaction occurs in membrane raft; interaction increases
CC markedly after store depletion; positively regulates SOCE-induced
CC adenylate cyclase activity; contributes to the targeting of ADCY8 to
CC discrete regions of the plasma membrane that are shielded from other
CC calcium events. Interacts with STIM1. Interacts with actin; interaction
CC is calcium independent; interaction is affected by calcium-calmodulin;
CC interaction controls the distribution and regulation of ADCY8.
CC Interacts with calmodulin; at rest, interacts via N-terminal domain;
CC upon a calcium rise, calmodulin becomes calcium-saturated and
CC subsequently binds to the C-terminal domain forming an autoinhibitory
CC complex; fully calcium-saturated calmodulin leaves the N-terminal
CC domain, binding solely to the C-terminal domain leading to dissociation
CC of autoinhibitory complex and resulting in activation of adenylate
CC cyclase; antagonizes interaction with PPP2CA; interaction is calcium
CC dependent. Interacts with PPP2R5D (By similarity).
CC {ECO:0000250|UniProtKB:P40146, ECO:0000269|PubMed:19158400}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14585998};
CC Multi-pass membrane protein. Basolateral cell membrane
CC {ECO:0000269|PubMed:14585998}. Apical cell membrane
CC {ECO:0000269|PubMed:14585998}. Synapse {ECO:0000269|PubMed:14585998}.
CC Cell projection, dendrite {ECO:0000269|PubMed:14585998,
CC ECO:0000269|PubMed:17335981}. Cell projection, axon
CC {ECO:0000269|PubMed:14585998, ECO:0000269|PubMed:17335981}. Presynaptic
CC cell membrane {ECO:0000269|PubMed:17335981,
CC ECO:0000269|PubMed:18448650}. Postsynaptic density
CC {ECO:0000269|PubMed:17335981}. Membrane raft
CC {ECO:0000250|UniProtKB:P40146}. Membrane, coated pit
CC {ECO:0000250|UniProtKB:P40146}. Cytoplasmic vesicle, clathrin-coated
CC vesicle membrane {ECO:0000250|UniProtKB:P40146}. Membrane, caveola
CC {ECO:0000250|UniProtKB:P40146}. Note=Localized to dendritic arbors
CC (PubMed:17335981). Monomeric N-glycosylated species localizes in
CC membrane raft. In contrast, monomeric unglycosylated forms are enriched
CC in clathrin-coated pits and vesicles. Dimers are also localized outside
CC of membrane rafts. Membrane raft localization and integrity is
CC indispensable for CCE-stimulated adenylate cyclase activity (By
CC similarity). {ECO:0000250|UniProtKB:P40146,
CC ECO:0000269|PubMed:17335981}.
CC -!- TISSUE SPECIFICITY: Abundantly expressed within the olfactory bulb,
CC thalamus, habenula, CA1 region of the hippocampus, and hypothalamus
CC (PubMed:10864938). Strongly expressed in pyramidal cells of CA1 and
CC weakly in CA3 and the dentate gyrus. Strongly and homogeneously
CC expressed in all cell layers of the anterior cingulate cortex (ACC).
CC Widely expressed in the insular cortex. Weakly expressed in the spinal
CC dorsal horn (PubMed:12441059). Abundantly present in the CA1/CA2 region
CC in the hippocampus neonatal and intensifies by adulthood. Weakly
CC expressed in the cerebellum at postnatal day 7 and decreased further by
CC postnatal day 14 (PubMed:17335981). {ECO:0000269|PubMed:10864938,
CC ECO:0000269|PubMed:12441059, ECO:0000269|PubMed:17335981}.
CC -!- DOMAIN: The protein contains two modules with six transmembrane helices
CC each; both are required for catalytic activity. Isolated N-terminal or
CC C-terminal guanylate cyclase domains have no catalytic activity, but
CC when they are brought together, enzyme activity is restored. The active
CC site is at the interface of the two domains. Both contribute substrate-
CC binding residues, but the catalytic metal ions are bound exclusively
CC via the N-terminal guanylate cyclase domain. The two transmembrane
CC clusters are necessary and suficient for the plasma membrane targeting
CC and oligomers assembly. The N-terminal and C-terminal domains interact
CC at rest as part of a larger autoinhibitory complex, with calmodulin
CC pre-associated at the N-terminal domain; the binding is specifically
CC inhibited by fully calcium-saturated calmodulin, resulting in
CC activation of AC8. {ECO:0000250|UniProtKB:P40146}.
CC -!- PTM: Phosphorylated by PKA; mediates inhibition of adenylate cyclase
CC activity at membrane raft; does not influence either CALM1 or PPP2CA
CC interaction with ADCY8. {ECO:0000250|UniProtKB:P40146}.
CC -!- PTM: N-glycosylated; N-glycosylation is responsible for raft-targeting;
CC is not necessary for CCE-stimulated adenylate cyclase activity.
CC {ECO:0000250|UniProtKB:P40146}.
CC -!- DISRUPTION PHENOTYPE: Adcy8 knockout mice are fertile and seem normal.
CC However mice reveal a tendency for both male and female to be somewhat
CC smaller from day of life 45 and 30 respectively while food intake is
CC normal. From there, females remain 10-15% smaller. In contrast, male
CC transiently grew more slowly between day of life 45 and 92, after which
CC point differences are not significant. Mice are less nervous.
CC {ECO:0000269|PubMed:10864938}.
CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
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DR EMBL; U85021; AAB41885.1; -; mRNA.
DR EMBL; AC116996; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC160934; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466545; EDL29360.1; -; Genomic_DNA.
DR EMBL; CH466545; EDL29361.1; -; Genomic_DNA.
DR CCDS; CCDS27506.1; -.
DR RefSeq; NP_033753.2; NM_009623.2.
DR AlphaFoldDB; P97490; -.
DR SMR; P97490; -.
DR BioGRID; 197977; 4.
DR CORUM; P97490; -.
DR STRING; 10090.ENSMUSP00000023007; -.
DR GlyCosmos; P97490; 3 sites, No reported glycans.
DR GlyGen; P97490; 3 sites.
DR iPTMnet; P97490; -.
DR PhosphoSitePlus; P97490; -.
DR MaxQB; P97490; -.
DR PaxDb; 10090-ENSMUSP00000023007; -.
DR PeptideAtlas; P97490; -.
DR ProteomicsDB; 285725; -.
DR Antibodypedia; 4355; 248 antibodies from 30 providers.
DR DNASU; 11514; -.
DR Ensembl; ENSMUST00000023007.7; ENSMUSP00000023007.6; ENSMUSG00000022376.9.
DR GeneID; 11514; -.
DR KEGG; mmu:11514; -.
DR UCSC; uc007vzo.1; mouse.
DR AGR; MGI:1341110; -.
DR CTD; 114; -.
DR MGI; MGI:1341110; Adcy8.
DR VEuPathDB; HostDB:ENSMUSG00000022376; -.
DR eggNOG; KOG3619; Eukaryota.
DR GeneTree; ENSGT00940000158742; -.
DR HOGENOM; CLU_001072_3_0_1; -.
DR InParanoid; P97490; -.
DR OMA; TTEWIPE; -.
DR OrthoDB; 3686360at2759; -.
DR PhylomeDB; P97490; -.
DR TreeFam; TF313845; -.
DR BRENDA; 4.6.1.1; 3474.
DR Reactome; R-MMU-163615; PKA activation.
DR Reactome; R-MMU-170660; Adenylate cyclase activating pathway.
DR Reactome; R-MMU-170670; Adenylate cyclase inhibitory pathway.
DR Reactome; R-MMU-418597; G alpha (z) signalling events.
DR Reactome; R-MMU-5610787; Hedgehog 'off' state.
DR BioGRID-ORCS; 11514; 0 hits in 78 CRISPR screens.
DR PRO; PR:P97490; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; P97490; Protein.
DR Bgee; ENSMUSG00000022376; Expressed in ventral lateral nucleus of thalamus and 135 other cell types or tissues.
DR ExpressionAtlas; P97490; baseline and differential.
DR Genevisible; P97490; MM.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0030424; C:axon; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0005901; C:caveola; ISS:UniProtKB.
DR GO; GO:0005905; C:clathrin-coated pit; ISS:UniProtKB.
DR GO; GO:0030665; C:clathrin-coated vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030425; C:dendrite; IDA:UniProtKB.
DR GO; GO:0060076; C:excitatory synapse; IDA:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; IDA:SynGO.
DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR GO; GO:0032809; C:neuronal cell body membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0044853; C:plasma membrane raft; ISS:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; IDA:UniProtKB.
DR GO; GO:0048786; C:presynaptic active zone; IDA:UniProtKB.
DR GO; GO:0042734; C:presynaptic membrane; IDA:SynGO.
DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IDA:SynGO.
DR GO; GO:0003779; F:actin binding; ISS:UniProtKB.
DR GO; GO:0004016; F:adenylate cyclase activity; IMP:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008294; F:calcium- and calmodulin-responsive adenylate cyclase activity; IMP:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0019902; F:phosphatase binding; ISO:MGI.
DR GO; GO:0046983; F:protein dimerization activity; ISS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISS:UniProtKB.
DR GO; GO:0034199; P:activation of protein kinase A activity; ISS:UniProtKB.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:MGI.
DR GO; GO:0006171; P:cAMP biosynthetic process; ISO:MGI.
DR GO; GO:0019933; P:cAMP-mediated signaling; ISO:MGI.
DR GO; GO:0071277; P:cellular response to calcium ion; ISS:UniProtKB.
DR GO; GO:1904322; P:cellular response to forskolin; ISS:UniProtKB.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; IDA:MGI.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0071315; P:cellular response to morphine; IMP:UniProtKB.
DR GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0010255; P:glucose mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0007626; P:locomotory behavior; IMP:UniProtKB.
DR GO; GO:0007616; P:long-term memory; IGI:MGI.
DR GO; GO:0007613; P:memory; IMP:UniProtKB.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IDA:SynGO.
DR GO; GO:0150076; P:neuroinflammatory response; IMP:UniProtKB.
DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; ISS:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IDA:MGI.
DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IMP:UniProtKB.
DR GO; GO:1900454; P:positive regulation of long-term synaptic depression; IMP:UniProtKB.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IMP:UniProtKB.
DR GO; GO:0031915; P:positive regulation of synaptic plasticity; IMP:UniProtKB.
DR GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB.
DR GO; GO:0080135; P:regulation of cellular response to stress; IMP:UniProtKB.
DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; IMP:UniProtKB.
DR CDD; cd07302; CHD; 2.
DR Gene3D; 3.30.70.1230; Nucleotide cyclase; 2.
DR InterPro; IPR001054; A/G_cyclase.
DR InterPro; IPR018297; A/G_cyclase_CS.
DR InterPro; IPR032628; AC_N.
DR InterPro; IPR030672; Adcy.
DR InterPro; IPR009398; Adcy_conserved_dom.
DR InterPro; IPR029787; Nucleotide_cyclase.
DR PANTHER; PTHR45627; ADENYLATE CYCLASE TYPE 1; 1.
DR PANTHER; PTHR45627:SF1; ADENYLATE CYCLASE TYPE 8; 1.
DR Pfam; PF16214; AC_N; 1.
DR Pfam; PF06327; Adcy_cons_dom; 1.
DR Pfam; PF00211; Guanylate_cyc; 2.
DR PIRSF; PIRSF039050; Ade_cyc; 1.
DR SMART; SM00044; CYCc; 2.
DR SUPFAM; SSF55073; Nucleotide cyclase; 2.
DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 2.
DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 2.
PE 1: Evidence at protein level;
KW ATP-binding; cAMP biosynthesis; Cell membrane; Cell projection; Coated pit;
KW Cytoplasmic vesicle; Glycoprotein; Lyase; Magnesium; Manganese; Membrane;
KW Metal-binding; Methylation; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..1249
FT /note="Adenylate cyclase type 8"
FT /id="PRO_0000195706"
FT TOPO_DOM 1..180
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 181..201
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 210..230
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 245..265
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 272..292
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 294..314
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 319..339
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 340..713
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 714..734
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 736..756
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 785..805
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 829..849
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 859..879
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 892..912
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 913..1249
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..180
FT /note="Involved in ORAI1, STIM1, PPP2CA and PPP2R1A
FT interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 1..107
FT /note="Involved in AKAP5 and PRKAR2A interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 14..33
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 50..118
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1107..1249
FT /note="Involved in CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 1198..1213
FT /note="Required for both calcium stimulation and
FT maintenance of autoinhibition"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 1221..1249
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 38..40
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT MOTIF 49..51
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT COMPBIAS 68..87
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 417..422
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 417
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 417
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 418
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 459..461
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 461
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 461
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 505
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 1032
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1107..1109
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1114..1118
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1154
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT SITE 1197
FT /note="Essential for autoinhibition maintenance by
FT promoting interaction of the N and C termini"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1198
FT /note="Essential for autoinhibition maintenance"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1201
FT /note="Essential for autoinhibition maintenance by
FT promoting interaction of the N and C termini"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1203
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1205
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT MOD_RES 55
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 612
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 622
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 815
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 819
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 886
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CONFLICT 24
FT /note="A -> V (in Ref. 1; AAB41885)"
FT /evidence="ECO:0000305"
FT CONFLICT 59
FT /note="G -> C (in Ref. 1; AAB41885)"
FT /evidence="ECO:0000305"
FT CONFLICT 849
FT /note="L -> V (in Ref. 1; AAB41885)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1249 AA; 140095 MW; 26103B6E0DB9C701 CRC64;
MELSDVHCLS GSEELYTIQP TPPAGDDGSG SRPQRLLWQT AVRHITEQRF IHGHRGGGGG
GVSRKASNPA GSGPNHHAPQ LSSDSVLPLY SLGPGERAHN TGGTKVFPER SGSGSASGSG
GGGDLGFLHL DCAPSNSDFF LNGGYSYRGV IFPTLRNSFK SRDLERLYQR YFLGQRRKSE
VVMNVLDVLT KLTLLVLHLS LASAPMDPLK GILLGFFTGI EVVICALVVV RKDNTSHTYL
QYSGVVTWVA MTTQILAAGL GYGLLGDGIG YVLFTLFATY SMLPLPLTWA ILAGLGTSLL
QVTLQVLIPR LAVFSINQVL AQVVLFMCMN TAGIFISYLS DRAQRQAFLE TRRCVEARLR
LETENQRQER LVLSVLPRFV VLEMINDMTN VEDEHLQHQF HRIYIHRYEN VSILFADVKG
FTNLSTTLSA QELVRMLNEL FARFDRLAHE HHCLRIKILG DCYYCVSGLP EPRRDHAHCC
VEMGLSMIKT IRFVRSRTKH DVDMRIGIHS GSVLCGVLGL RKWQFDVWSW DVDIANKLES
GGIPGRIHIS KATLDCLNGD YNVEEGHGKE RNEFLRKHNI ETYLIKQPEE SLLCLPEDIV
KESVSCSDRR NSGATFTEGS WSPELPFDNI VGKQNTLAAL TRNSINLLPN HLAQALHVQS
GPEEINKRIE HTIDLRSGDK LRREHIKPFS LMFKDSSLEH KYSQMRDEVF KSNLVCAFIV
LLFITAIQSL LPSSRLMPMT IQFSILIMLH SALVLITTAE DYKCLPLILR KTCCWINETY
LARNVIIFAS ILINFLGAVL NILWCDFDKS IPLKNLTFNS SAVFTDICSY PEYFVFTGVL
AMVTCAVFLR LNSVLKLAVL LIMIAIYALL TETIYAGLFL SYDNLNHSGE DFLGTKEASL
LLMAMFLLAV FYHGQQLEYT ARLDFLWRVQ AKEEINEMKE LREHNENMLR NILPSHVARH
FLEKDRDNEE LYSQSYDAVG VMFASIPGFA DFYSQTEMNN QGVECLRLLN EIIADFDELL
GEDRFQDIEK IKTIGSTYMA VSGLSPEKQQ CEDKWGHLCA LADFSLALTE SIQEINKHSF
NNFELRIGIS HGSVVAGVIG AKKPQYDIWG KTVNLASRMD STGVSGRIQV PEETYLILKD
QGFAFDYRGE IYVKGISEQE GKIKTYFLLG RVQPNPFILP PRRLPGQYSL AAVVLGLVQS
LNRQRQKQLL NENSNSGIIK SHYNRRTLLT PSGPEPGAQA EGTDKSDLP
//
