ADCY8_RAT
ID ADCY8_RAT Reviewed; 1248 AA.
AC P40146;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Adenylate cyclase type 8 {ECO:0000305};
DE EC=4.6.1.1 {ECO:0000269|PubMed:8163524, ECO:0000269|PubMed:8557635};
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:0000303|PubMed:16741924};
DE AltName: Full=Ca(2+)/calmodulin-activated adenylyl cyclase;
GN Name=Adcy8 {ECO:0000312|RGD:2036};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=8163524; DOI=10.1016/s0021-9258(17)32700-x;
RA Cali J.J., Zwaagstra J.C., Mons N., Cooper D.M., Krupinski J.;
RT "Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed
RT in discrete regions of rat brain.";
RL J. Biol. Chem. 269:12190-12195(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), TISSUE SPECIFICITY,
RP GLYCOSYLATION (ISOFORMS 1 AND 3), ACTIVITY REGULATION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR.
RX PubMed=8557635; DOI=10.1074/jbc.271.2.1089;
RA Cali J.J., Parekh R.S., Krupinski J.;
RT "Splice variants of type VIII adenylyl cyclase. Differences in
RT glycosylation and regulation by Ca2+/calmodulin.";
RL J. Biol. Chem. 271:1089-1095(1996).
RN [3]
RP SUBUNIT, AND DOMAIN.
RX PubMed=11856299; DOI=10.1046/j.0014-2956.2001.02708.x;
RA Gu C., Cali J.J., Cooper D.M.;
RT "Dimerization of mammalian adenylate cyclases.";
RL Eur. J. Biochem. 269:413-421(2002).
RN [4]
RP MUTAGENESIS OF 38-TRP--THR-40 AND 49-ARG--ILE-51, ACTIVITY REGULATION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=11744699; DOI=10.1074/jbc.m109615200;
RA Smith K.E., Gu C., Fagan K.A., Hu B., Cooper D.M.;
RT "Residence of adenylyl cyclase type 8 in caveolae is necessary but not
RT sufficient for regulation by capacitative Ca(2+) entry.";
RL J. Biol. Chem. 277:6025-6031(2002).
RN [5]
RP ACTIVITY REGULATION, FUNCTION, TISSUE SPECIFICITY, AND ALTERNATIVE SPLICING
RP (ISOFORM 4).
RX PubMed=13680124; DOI=10.1007/s00125-003-1203-8;
RA Delmeire D., Flamez D., Hinke S.A., Cali J.J., Pipeleers D., Schuit F.;
RT "Type VIII adenylyl cyclase in rat beta cells: coincidence signal
RT detector/generator for glucose and GLP-1.";
RL Diabetologia 46:1383-1393(2003).
RN [6]
RP ACTIVITY REGULATION.
RX PubMed=16186630; DOI=10.1385/jmn:27:2:195;
RA Steiner D., Avidor-Reiss T., Schallmach E., Saya D., Vogel Z.;
RT "Inhibition and superactivation of the calcium-stimulated isoforms of
RT adenylyl cyclase: role of Gbetagamma dimers.";
RL J. Mol. Neurosci. 27:195-203(2005).
RN [7]
RP INDUCTION, AND FUNCTION.
RX PubMed=16741924; DOI=10.1002/jcp.20673;
RA Clement N., Glorian M., Raymondjean M., Andreani M., Limon I.;
RT "PGE2 amplifies the effects of IL-1beta on vascular smooth muscle cell de-
RT differentiation: a consequence of the versatility of PGE2 receptors 3 due
RT to the emerging expression of adenylyl cyclase 8.";
RL J. Cell. Physiol. 208:495-505(2006).
RN [8]
RP INTERACTION WITH PPP2CA; CALM1 AND PPP2R1A, REGION, MUTAGENESIS OF
RP 38-TRP--THR-40 AND 49-ARG--ILE-51, SUBCELLULAR LOCATION, AND MOTIF.
RX PubMed=16258073; DOI=10.1124/mol.105.018275;
RA Crossthwaite A.J., Ciruela A., Rayner T.F., Cooper D.M.;
RT "A direct interaction between the N terminus of adenylyl cyclase AC8 and
RT the catalytic subunit of protein phosphatase 2A.";
RL Mol. Pharmacol. 69:608-617(2006).
RN [9]
RP SUBUNIT, GLYCOSYLATION, MUTAGENESIS OF LEU-432; LEU-439; LEU-446; LEU-453;
RP ASN-814; ASN-818 AND ASN-885, ACTIVITY REGULATION, AND SUBCELLULAR
RP LOCATION.
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 [10]
RP REGION, MUTAGENESIS OF 38-TRP--THR-40; 49-ARG--ILE-51; LEU-1196; VAL-1197;
RP GLN-1198; SER-1199; LEU-1200; ARG-1202; ARG-1204; LYS-1206; LEU-1208 AND
RP LEU-1209, ACTIVITY REGULATION, SITE, DOMAIN, AND INTERACTION WITH
RP CALMODULIN.
RX PubMed=19305019; DOI=10.1074/jbc.m809585200;
RA Macdougall D.A., Wachten S., Ciruela A., Sinz A., Cooper D.M.;
RT "Separate elements within a single IQ-like motif in adenylyl cyclase type 8
RT impart ca2+/calmodulin binding and autoinhibition.";
RL J. Biol. Chem. 284:15573-15588(2009).
RN [11]
RP SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=19171672; DOI=10.1124/mol.108.051748;
RA Martin A.C., Willoughby D., Ciruela A., Ayling L.J., Pagano M., Wachten S.,
RA Tengholm A., Cooper D.M.;
RT "Capacitative Ca2+ entry via Orai1 and stromal interacting molecule 1
RT (STIM1) regulates adenylyl cyclase type 8.";
RL Mol. Pharmacol. 75:830-842(2009).
RN [12]
RP INTERACTION WITH AKAP5, AND ACTIVITY REGULATION.
RX PubMed=20410303; DOI=10.1074/jbc.m110.120725;
RA Willoughby D., Masada N., Wachten S., Pagano M., Halls M.L., Everett K.L.,
RA Ciruela A., Cooper D.M.;
RT "AKAP79/150 interacts with AC8 and regulates Ca2+-dependent cAMP synthesis
RT in pancreatic and neuronal systems.";
RL J. Biol. Chem. 285:20328-20342(2010).
RN [13]
RP INDUCTION, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21046358; DOI=10.1007/s00125-010-1955-x;
RA Roger B., Papin J., Vacher P., Raoux M., Mulot A., Dubois M.,
RA Kerr-Conte J., Voy B.H., Pattou F., Charpentier G., Jonas J.C.,
RA Moustaid-Moussa N., Lang J.;
RT "Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and
RT effects of chronically elevated glucose in rat and human pancreatic beta
RT cells.";
RL Diabetologia 54:390-402(2011).
RN [14]
RP INTERACTION WITH AKAP5, PHOSPHORYLATION, AND ACTIVITY REGULATION.
RX PubMed=21771783; DOI=10.1074/jbc.m111.243899;
RA Delint-Ramirez I., Willoughby D., Hammond G.V., Ayling L.J., Cooper D.M.;
RT "Palmitoylation targets AKAP79 protein to lipid rafts and promotes its
RT regulation of calcium-sensitive adenylyl cyclase type 8.";
RL J. Biol. Chem. 286:32962-32975(2011).
RN [15]
RP MUTAGENESIS OF 1-MET--PHE-106 AND ASP-416, AND INTERACTION WITH ACTIN AND
RP CALM1.
RX PubMed=22399809; DOI=10.1242/jcs.091090;
RA Ayling L.J., Briddon S.J., Halls M.L., Hammond G.R., Vaca L., Pacheco J.,
RA Hill S.J., Cooper D.M.;
RT "Adenylyl cyclase AC8 directly controls its micro-environment by recruiting
RT the actin cytoskeleton in a cholesterol-rich milieu.";
RL J. Cell Sci. 125:869-886(2012).
RN [16]
RP ACTIVITY REGULATION, INTERACTION WITH PRKAR2A; PPP2CA; PPP2R5D AND AKAP5,
RP REGION, MUTAGENESIS OF SER-66; SER-112; SER-178; SER-611; SER-852 AND
RP SER-1120, AND PHOSPHORYLATION.
RX PubMed=22976297; DOI=10.1242/jcs.111427;
RA Willoughby D., Halls M.L., Everett K.L., Ciruela A., Skroblin P.,
RA Klussmann E., Cooper D.M.;
RT "A key phosphorylation site in AC8 mediates regulation of Ca(2+)-dependent
RT cAMP dynamics by an AC8-AKAP79-PKA signalling complex.";
RL J. Cell Sci. 125:5850-5859(2012).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-621, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [18]
RP INTERACTION WITH ORAI1 AND STIM1, REGION, SUBCELLULAR LOCATION, FUNCTION,
RP AND ACTIVITY REGULATION.
RX PubMed=22494970; DOI=10.1126/scisignal.2002299;
RA Willoughby D., Everett K.L., Halls M.L., Pacheco J., Skroblin P., Vaca L.,
RA Klussmann E., Cooper D.M.;
RT "Direct binding between Orai1 and AC8 mediates dynamic interplay between
RT Ca2+ and cAMP signaling.";
RL Sci. Signal. 5:RA29-RA29(2012).
RN [19]
RP ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=24086669; DOI=10.1371/journal.pone.0075942;
RA Everett K.L., Cooper D.M.;
RT "An improved targeted cAMP sensor to study the regulation of adenylyl
RT cyclase 8 by Ca2+ entry through voltage-gated channels.";
RL PLoS ONE 8:E75942-E75942(2013).
RN [20]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=25381556; DOI=10.1007/s00125-014-3437-z;
RA Dou H., Wang C., Wu X., Yao L., Zhang X., Teng S., Xu H., Liu B., Wu Q.,
RA Zhang Q., Hu M., Wang Y., Wang L., Wu Y., Shang S., Kang X., Zheng L.,
RA Zhang J., Raoux M., Lang J., Li Q., Su J., Yu X., Chen L., Zhou Z.;
RT "Calcium influx activates adenylyl cyclase 8 for sustained insulin
RT secretion in rat pancreatic beta cells.";
RL Diabetologia 58:324-333(2015).
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:8163524,
CC PubMed:24086669, PubMed:22494970, PubMed:21046358, PubMed:13680124,
CC PubMed:25381556). Plays a role in many brain functions, such as
CC learning, memory, drug addiction, and anxiety modulation through
CC regulation of synaptic plasticity by modulating long-term memory and
CC long-term potentiation (LTP) through CREB transcription factor activity
CC modulation (PubMed:8163524). Plays a central role in insulin secretion
CC by controlling glucose homeostasis through glucagon-like peptide 1 and
CC glucose signaling pathway and maintains insulin secretion through
CC calcium-dependent PKA activation leading to vesicle pool replenishment
CC (PubMed:21046358, PubMed:13680124, PubMed:25381556). Also, allows
CC PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by
CC switching from a negative to a positive regulation, during the IL1B
CC induced-dedifferentiation of smooth muscle cells (PubMed:16741924).
CC {ECO:0000269|PubMed:13680124, ECO:0000269|PubMed:16741924,
CC ECO:0000269|PubMed:21046358, ECO:0000269|PubMed:22494970,
CC ECO:0000269|PubMed:24086669, ECO:0000269|PubMed:25381556,
CC ECO:0000269|PubMed:8163524}.
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:0000269|PubMed:8163524, ECO:0000269|PubMed:8557635};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:8557635};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:8557635};
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:8163524,
CC PubMed:8557635, PubMed:19305019). In non-excitable cells, activated by
CC capacitative calcium entry (CCE) through store-operated channels,
CC namely through interaction with ORAI1 and STIM1; membrane raft and
CC caveolae localization and membrane integrity are indispensable
CC (PubMed:19158400, PubMed:11744699, PubMed:19171672, PubMed:22494970,
CC PubMed:20410303). 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
CC (PubMed:20410303). In excitable cells, activated during membrane
CC depolarization through L-type voltage-gated calcium channels (VGCC),
CC leading to calcium entry; the L-type alpha subunit is sufficient
CC (PubMed:24086669, PubMed:25381556). Activated via stimulation of the
CC GLP1R (PubMed:25381556). Synergistically activated by
CC calcium/calmodulin and GNAS (PubMed:13680124). Stimulated by forskolin
CC (PubMed:16186630, PubMed:13680124). Inhibited by PKA directly bound to
CC AKAP5 at membrane raft (PubMed:22976297, PubMed:21771783). Inhibition
CC by acute activation of OPRM1 and activation by chronic activation of
CC OPRM1 is mediated by pertussis toxin-sensitive G(i) and G(o) G alpha
CC proteins and G beta-gamma dimer. Activity is inhibited by G beta-gamma
CC dimer (PubMed:16186630). {ECO:0000269|PubMed:11744699,
CC ECO:0000269|PubMed:13680124, ECO:0000269|PubMed:16186630,
CC ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:19171672,
CC ECO:0000269|PubMed:19305019, ECO:0000269|PubMed:20410303,
CC ECO:0000269|PubMed:21771783, ECO:0000269|PubMed:22494970,
CC ECO:0000269|PubMed:22976297, ECO:0000269|PubMed:24086669,
CC ECO:0000269|PubMed:25381556, ECO:0000269|PubMed:8163524,
CC ECO:0000269|PubMed:8557635}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.18 mM for ATP (in the presence of 5.74 mM free Mg(2+) and 1 muM
CC exogenous calmodulin) (isoform 1) {ECO:0000269|PubMed:8557635};
CC KM=0.16 mM for ATP (in the presence of 5.74 mM free Mg(2+) and 1 muM
CC exogenous calmodulin) (isoform 2) {ECO:0000269|PubMed:8557635};
CC KM=2.10 mM for ATP (in the presence of 5.74 mM free Mg(2+) and 1 muM
CC exogenous calmodulin) (isoform 3) {ECO:0000269|PubMed:8557635};
CC KM=0.038 mM for ATP (in the presence of 0.23 mM free Mn(2+) and 1 muM
CC exogenous calmodulin) (isoform 1) {ECO:0000269|PubMed:8557635};
CC KM=0.025 mM for ATP (in the presence of 0.23 mM free Mn(2+) and 1 muM
CC exogenous calmodulin) (isoform 2) {ECO:0000269|PubMed:8557635};
CC KM=0.116 mM for ATP (in the presence of 0.23 mM free Mn(2+) and 1 muM
CC exogenous calmodulin) (isoform 3) {ECO:0000269|PubMed:8557635};
CC Vmax=7.4 nmol/min/mg enzyme (in the presence of 5.74 mM free Mg(2+)
CC and 1 muM exogenous calmodulin) (isoform 1)
CC {ECO:0000269|PubMed:8557635};
CC Vmax=2 nmol/min/mg enzyme (in the presence of 5.74 mM free Mg(2+) and
CC 1 muM exogenous calmodulin) (isoform 2) {ECO:0000269|PubMed:8557635};
CC Vmax=1.5 nmol/min/mg enzyme (in the presence of 5.74 mM free Mg(2+)
CC and 1 muM exogenous calmodulin) (isoform 3)
CC {ECO:0000269|PubMed:8557635};
CC Vmax=10.4 nmol/min/mg enzyme (in the presence of 0.23 mM free Mn(2+)
CC and 1 muM exogenous calmodulin) (isoform 1)
CC {ECO:0000269|PubMed:8557635};
CC Vmax=3.5 nmol/min/mg enzyme (in the presence of 0.23 mM free Mn(2+)
CC and 1 muM exogenous calmodulin) (isoform 2)
CC {ECO:0000269|PubMed:8557635};
CC Vmax=1.5 nmol/min/mg enzyme (in the presence of 0.23 mM free Mn(2+)
CC and 1 muM exogenous calmodulin) (isoform 3)
CC {ECO:0000269|PubMed:8557635};
CC -!- SUBUNIT: Homodimer; via transmembrane domain (PubMed:19158400,
CC PubMed:11856299). Monomer (PubMed:19158400). Heterodimer
CC (PubMed:11856299). Oligemer; via transmembrane domain
CC (PubMed:11856299). Interacts with PRKAR2A and AKAP5; inhibits adenylate
CC cyclase activity through PKA phosphorylation (PubMed:22976297).
CC Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory
CC effects of PKA on adenylate cyclase activity; interaction is dependent
CC of catalytically active PPP2CA; antagonizes interaction with calmodulin
CC (PubMed:22976297, PubMed:16258073). Interacts with AKAP5 (palmitoylated
CC form); promotes the phosphorylation of ADCY8 after store-operated
CC calcium entry (SOCE) stimulation at membrane raft (PubMed:21771783,
CC PubMed:20410303). Interacts with ORAI1; interaction is calcium store
CC depletion independent; interaction occurs in membrane raft; interaction
CC increases markedly after store depletion; positively regulates SOCE-
CC induced adenylate cyclase activity; contributes to the targeting of
CC ADCY8 to discrete regions of the plasma membrane that are shielded from
CC other calcium events (PubMed:22494970). Interacts with STIM1
CC (PubMed:22494970). Interacts with actin; interaction is calcium
CC independent; interaction is affected by calcium-calmodulin; interaction
CC controls the distribution and regulation of ADCY8 (PubMed:22399809).
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 (PubMed:19305019, PubMed:16258073, PubMed:22399809).
CC Interacts with PPP2R5D (PubMed:22976297). {ECO:0000269|PubMed:11856299,
CC ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19158400,
CC ECO:0000269|PubMed:19305019, ECO:0000269|PubMed:20410303,
CC ECO:0000269|PubMed:21771783, ECO:0000269|PubMed:22399809,
CC ECO:0000269|PubMed:22494970, ECO:0000269|PubMed:22976297}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19171672,
CC ECO:0000269|PubMed:21046358, ECO:0000269|PubMed:8163524}; Multi-pass
CC membrane protein. Cell projection, dendrite
CC {ECO:0000269|PubMed:16258073}. Membrane raft
CC {ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19158400,
CC ECO:0000269|PubMed:19171672, ECO:0000269|PubMed:22494970}. Membrane,
CC coated pit {ECO:0000269|PubMed:19158400}. Cytoplasmic vesicle,
CC clathrin-coated vesicle membrane {ECO:0000269|PubMed:19158400}.
CC Membrane, caveola {ECO:0000269|PubMed:11744699}. Basolateral cell
CC membrane {ECO:0000250|UniProtKB:P97490}. Apical cell membrane
CC {ECO:0000250|UniProtKB:P97490}. Synapse {ECO:0000250|UniProtKB:P97490}.
CC Cell projection, dendrite {ECO:0000250|UniProtKB:P97490}. Cell
CC projection, axon {ECO:0000250|UniProtKB:P97490}. Presynaptic cell
CC membrane {ECO:0000250|UniProtKB:P97490}. Postsynaptic density
CC {ECO:0000250|UniProtKB:P97490}. Note=Localized to dendritic arbors (By
CC similarity). Monomeric N-glycosylated specieslocalized in membrane
CC raft. In contrast, monomeric unglycosylated forms are enriched in
CC clathrin-coated pits and vesicles. Dimers are also localized outside of
CC membrane rafts. Membrane raft localization and integrity is
CC indispensable for CCE-stimulated adenylate cyclase activity
CC (PubMed:19158400). {ECO:0000250|UniProtKB:P97490,
CC ECO:0000269|PubMed:19158400}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=VIII-A {ECO:0000303|PubMed:8557635};
CC IsoId=P40146-1; Sequence=Displayed;
CC Name=2; Synonyms=VIII-B {ECO:0000303|PubMed:8557635};
CC IsoId=P40146-2; Sequence=VSP_059987;
CC Name=3; Synonyms=VIII-c {ECO:0000303|PubMed:8557635};
CC IsoId=P40146-3; Sequence=VSP_059986;
CC Name=4; Synonyms=VIII-D {ECO:0000303|PubMed:13680124};
CC IsoId=P40146-4; Sequence=VSP_059986, VSP_059987;
CC -!- TISSUE SPECIFICITY: Brain (PubMed:13680124, PubMed:8557635). Expressed
CC in insulin-producing cells (PubMed:13680124).
CC {ECO:0000269|PubMed:13680124, ECO:0000269|PubMed:8557635}.
CC -!- INDUCTION: Reduces by glucose (PubMed:21046358). Up-regulated during
CC vascular smooth muscle cell de-differentiation by IL1B
CC (PubMed:16741924). {ECO:0000269|PubMed:16741924,
CC ECO:0000269|PubMed:21046358}.
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 (PubMed:11856299). The N-terminal and C-terminal
CC domains interact at rest as part of a larger autoinhibitory complex,
CC with calmodulin pre-associated at the N-terminal domain; the binding is
CC specifically inhibited by fully calcium-saturated calmodulin, resulting
CC in activation of AC8 (PubMed:19305019). {ECO:0000250|UniProtKB:P26769,
CC ECO:0000269|PubMed:11856299, ECO:0000269|PubMed:19305019}.
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:0000269|PubMed:21771783,
CC ECO:0000269|PubMed:22976297}.
CC -!- PTM: [Isoform 1]: N-glycosylated; N-glycosylation is responsible for
CC raft-targeting; is not necessary for CCE-stimulated adenylate cyclase
CC activity. {ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:8557635}.
CC -!- PTM: [Isoform 3]: N-glycosylated; N-glycosylation is responsible for
CC raft-targeting; is not necessary for CCE-stimulated adenylate cyclase
CC activity. {ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:8557635}.
CC -!- MISCELLANEOUS: [Isoform 3]: EC50 is approximately 4 times more
CC sensitive to stimulation by calcium/calmodulin than isoform 1 and 2.
CC {ECO:0000269|PubMed:8557635}.
CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
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DR EMBL; L26986; AAA20504.1; -; mRNA.
DR PIR; A53588; A53588.
DR RefSeq; NP_058838.1; NM_017142.1. [P40146-1]
DR AlphaFoldDB; P40146; -.
DR SMR; P40146; -.
DR STRING; 10116.ENSRNOP00000006789; -.
DR BindingDB; P40146; -.
DR ChEMBL; CHEMBL2095179; -.
DR DrugCentral; P40146; -.
DR GlyGen; P40146; 3 sites.
DR iPTMnet; P40146; -.
DR PhosphoSitePlus; P40146; -.
DR PaxDb; P40146; -.
DR PRIDE; P40146; -.
DR GeneID; 29241; -.
DR KEGG; rno:29241; -.
DR UCSC; RGD:2036; rat. [P40146-1]
DR CTD; 114; -.
DR RGD; 2036; Adcy8.
DR eggNOG; KOG3619; Eukaryota.
DR InParanoid; P40146; -.
DR OrthoDB; 107368at2759; -.
DR PhylomeDB; P40146; -.
DR BRENDA; 4.6.1.1; 5301.
DR Reactome; R-RNO-163615; PKA activation.
DR Reactome; R-RNO-170660; Adenylate cyclase activating pathway.
DR Reactome; R-RNO-170670; Adenylate cyclase inhibitory pathway.
DR Reactome; R-RNO-418597; G alpha (z) signalling events.
DR Reactome; R-RNO-5610787; Hedgehog 'off' state.
DR PRO; PR:P40146; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0005901; C:caveola; IDA:UniProtKB.
DR GO; GO:0005905; C:clathrin-coated pit; IDA: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; ISS:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0099056; C:integral component of presynaptic membrane; ISO:RGD.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0032809; C:neuronal cell body membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0044853; C:plasma membrane raft; IDA:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR GO; GO:0048786; C:presynaptic active zone; ISS:UniProtKB.
DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; ISO:RGD.
DR GO; GO:0003779; F:actin binding; IDA:UniProtKB.
DR GO; GO:0004016; F:adenylate cyclase activity; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008294; F:calcium- and calmodulin-responsive adenylate cyclase activity; IDA:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0019902; F:phosphatase binding; IPI:UniProtKB.
DR GO; GO:0008022; F:protein C-terminus binding; IDA:RGD.
DR GO; GO:0046983; F:protein dimerization activity; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0047485; F:protein N-terminus binding; IDA:RGD.
DR GO; GO:0051721; F:protein phosphatase 2A binding; IDA:UniProtKB.
DR GO; GO:0034199; P:activation of protein kinase A activity; IMP:UniProtKB.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:WormBase.
DR GO; GO:0006171; P:cAMP biosynthetic process; IDA:RGD.
DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:RGD.
DR GO; GO:0071277; P:cellular response to calcium ion; IDA:UniProtKB.
DR GO; GO:1904322; P:cellular response to forskolin; IDA:UniProtKB.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; IMP:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0071315; P:cellular response to morphine; IDA:UniProtKB.
DR GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0010255; P:glucose mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR GO; GO:0007616; P:long-term memory; ISO:RGD.
DR GO; GO:0007613; P:memory; ISS:UniProtKB.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; ISO:RGD.
DR GO; GO:0150076; P:neuroinflammatory response; ISS:UniProtKB.
DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IMP:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR GO; GO:0031915; P:positive regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0051259; P:protein complex oligomerization; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IMP:UniProtKB.
DR GO; GO:0080135; P:regulation of cellular response to stress; ISS:UniProtKB.
DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; ISS:UniProtKB.
DR GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR CDD; cd07302; CHD; 2.
DR Gene3D; 3.30.70.1230; -; 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 Pfam; PF16214; AC_N; 1.
DR Pfam; PF06327; DUF1053; 1.
DR Pfam; PF00211; Guanylate_cyc; 2.
DR PIRSF; PIRSF039050; Ade_cyc; 1.
DR SMART; SM00044; CYCc; 2.
DR SUPFAM; SSF55073; SSF55073; 2.
DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 2.
DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; cAMP biosynthesis; Cell membrane;
KW Cell projection; Coated pit; Cytoplasmic vesicle; Glycoprotein; Lyase;
KW Magnesium; Manganese; Membrane; Metal-binding; Methylation;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat; Synapse;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..1248
FT /note="Adenylate cyclase type 8"
FT /id="PRO_0000195707"
FT TOPO_DOM 1..179
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 180..200
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 209..229
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 244..264
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 271..291
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 293..313
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 318..338
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 339..712
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 713..733
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 735..755
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 784..804
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 828..848
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 858..878
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 891..911
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 912..1248
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..179
FT /note="Involved in ORAI1, STIM1, PPP2CA and PPP2R1A
FT interaction"
FT /evidence="ECO:0000269|PubMed:16258073,
FT ECO:0000269|PubMed:22494970, ECO:0000269|PubMed:22976297"
FT REGION 1..106
FT /note="Involved in AKAP5 and PRKAR2A interaction"
FT /evidence="ECO:0000269|PubMed:22976297"
FT REGION 51..117
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1106..1248
FT /note="Involved in CALM1 interaction"
FT /evidence="ECO:0000269|PubMed:16258073"
FT REGION 1197..1212
FT /note="Required for both calcium stimulation and
FT maintenance of autoinhibition"
FT /evidence="ECO:0000269|PubMed:19305019"
FT REGION 1220..1248
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 38..40
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000269|PubMed:16258073"
FT MOTIF 49..51
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000269|PubMed:16258073"
FT COMPBIAS 67..88
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 416..421
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 416
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 416
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 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 458..460
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 460
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 460
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 504
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 1031
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1106..1108
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1113..1117
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1153
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT SITE 1196
FT /note="Essential for autoinhibition maintenance by
FT promoting interaction of the N and C termini"
FT /evidence="ECO:0000269|PubMed:19305019"
FT SITE 1197
FT /note="Essential for autoinhibition maintenance"
FT /evidence="ECO:0000269|PubMed:19305019"
FT SITE 1200
FT /note="Essential for autoinhibition maintenance by
FT promoting interaction of the N and C termini"
FT /evidence="ECO:0000269|PubMed:19305019"
FT SITE 1202
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000269|PubMed:19305019"
FT SITE 1204
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000269|PubMed:19305019"
FT MOD_RES 55
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P97490"
FT MOD_RES 611
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97490"
FT MOD_RES 621
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT CARBOHYD 814
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 818
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 885
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 635..700
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000269|PubMed:13680124,
FT ECO:0000269|PubMed:8557635"
FT /id="VSP_059986"
FT VAR_SEQ 802..831
FT /note="Missing (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000269|PubMed:13680124,
FT ECO:0000269|PubMed:8557635"
FT /id="VSP_059987"
FT MUTAGEN 1..106
FT /note="Missing: Does not affect adenylate cyclase activity
FT in response to calcium in vitro. Reduces adenylate cyclase
FT activity in response to capacitative calcium entry (CCE).
FT Reduces colocalization with actin. Does not improve the
FT distribution of the actin cytoskeleton at the plasma
FT membrane."
FT /evidence="ECO:0000269|PubMed:22399809"
FT MUTAGEN 38..40
FT /note="WQT->AAA: Does not interacts with CALM1; when
FT associated with 49-A--A-51. Interacts with PPP2CA; when
FT associated with 49-A--A-51. Greatly reduces CCE-stimulated
FT adenylate cyclase activity; when associated with 49-A--A-
FT 51. Does not affect caveolar localization; when associated
FT with 49-A--A-51. Does not affect calcium/calmodulin
FT stimulated adenylate cyclase activity; when associated with
FT 49-A--A-51. Decreases calcium/calmodulin stimulated
FT adenylate cyclase activity; when associated with 49-A--A-
FT 51; A-1197; A-1198 and A-1202."
FT /evidence="ECO:0000269|PubMed:11744699,
FT ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19305019"
FT MUTAGEN 49..51
FT /note="RFI->AAA: Does not interacts with CALM1; when
FT associated with 38-A--A-40. Interacts with PPP2CA; when
FT associated with 38-A--A-40. Greatly reduces CCE-stimulated
FT adenylate cyclase activity; when associated with 38-A--A-
FT 40. Does not affect caveolar localization; when associated
FT with 38-A--A-40.Does not affect calcium/calmodulin
FT stimulated adenylate cyclase activity; when associated with
FT 38-A--A-40. Decreases calcium/calmodulin stimulated
FT adenylate cyclase activity; when associated with 38-A--A-
FT 40; A-1197; A-1198 and A-1202."
FT /evidence="ECO:0000269|PubMed:11744699,
FT ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19305019"
FT MUTAGEN 66
FT /note="S->A: Decraeses significantly the stimulatoty effect
FT of PKA inhibitor on calcium-stimulated adenylate cyclase
FT activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 112
FT /note="S->A: Loses the stimulatoty effect of PKA inhibitor
FT on calcium-stimulated adenylate cyclase activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 112
FT /note="S->D: Insensitive to the stimulatory effect of PKA
FT inhibitor on calcium-stimulated adenylate cyclase
FT activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 178
FT /note="S->A: Does not affect the stimulatoty effect of PKA
FT inhibitor on calcium-stimulated adenylate cyclase
FT activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 416
FT /note="D->N: Loses adenylate cyclase activity in response
FT to calcium."
FT /evidence="ECO:0000269|PubMed:22399809"
FT MUTAGEN 432
FT /note="L->A: Does not affect dimerization; when associated
FT with A-439. Dramatically reduces the levels of the N-
FT glycosylated monomeric species; when associated with A-439.
FT Loss of calcium- and calmodulin-responsive adenylate
FT cyclase activity; when associated with A-439. Affects
FT membrane raft localization; when associated with A-439."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 439
FT /note="L->A: Does not affect dimerization. Does not affect
FT dimerization;when associated with A-432. Does not affect
FT dimerization;when associated with A-446 and A-432. Does not
FT affect dimerization;when associated with A-432; A-446 and
FT A-453. Dramatically reduces the levels of the N-
FT glycosylated monomeric species. Dramatically reduces the
FT levels of the N-glycosylated monomeric species; when
FT associated with A-432.Dramatically reduces the levels of
FT the N-glycosylated monomeric species; when associated with
FT A-446 and A-432. Dramatically reduces the levels of the N-
FT glycosylated monomeric species; when associated with A-453;
FT A-432 and A-446. Loss of calcium- and calmodulin-responsive
FT adenylate cyclase activity. Loss of calcium- and
FT calmodulin-responsive adenylate cyclase activity; when
FT associated with A-432. Loss of calcium- and calmodulin-
FT responsive adenylate cyclase activity; when associated with
FT A-446 and A-432. Loss of calcium- and calmodulin-responsive
FT adenylate cyclase activity; when associated with A-453; A-
FT 432 and A-446. Affects membrane raft localization. Affects
FT membrane raft localization; when associated with A-432.
FT Affects membrane raft localization; when associated with A-
FT 446 and A-432. Affects membrane raft localization; when
FT associated with A-439; A-432 and A-446."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 446
FT /note="L->A: Does not affect dimerization; when associated
FT with A-439 and A-432. Dramatically reduces the levels of
FT the N-glycosylated monomeric species; when associated with
FT A-439 and A-432. Loss of calcium- and calmodulin-responsive
FT adenylate cyclase activity; when associated with A-439 and
FT A-432. Affects membrane raft localization; when associated
FT with A-439 and A-432."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 453
FT /note="L->A: Does not affect dimerization; when associated
FT with A-439; A-432 and A-446. Dramatically reduces the
FT levels of the N-glycosylated monomeric species; when
FT associated with A-439; A-432 and A-446. Loss of
FT calcium- and calmodulin-responsive adenylate cyclase
FT activity; when associated with A-439; A-432 and A-446.
FT Affects membrane raft localization; when associated with A-
FT 439; A-432 and A-446."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 611
FT /note="S->A: Does not affect the stimulatoty effect of PKA
FT inhibitoron calcium-stimulated adenylate cyclase activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 814
FT /note="N->Q: Does not affect deglycosylation. Does not
FT affect plasma membrane targeting; when associated with Q-
FT 818 and A-885. Affects membrane raft localization; when
FT associated with Q-818 and A-885. Does not affect CCE-
FT stimulated adenylate cyclase activity; when associated with
FT Q-818 and A-885."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 818
FT /note="N->Q: Does not affect deglycosylation. Does not
FT affect plasma membrane targeting; when associated with Q-
FT 814 and A-885. Affects membrane raft localization; when
FT associated with Q-814 and A-885. Does not affect CCE-
FT stimulated adenylate cyclase activity; when associated with
FT Q-814 and A-885."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 852
FT /note="S->A: Does not affect the stimulatoty effect of PKA
FT inhibitoron calcium-stimulated adenylate cyclase activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 885
FT /note="N->E: Does not affect deglycosylation. Does not
FT affect plasma membrane targeting; when associated with Q-
FT 814 and A-818. Affects membrane raft localization; when
FT associated with Q-814 and A-818. Does not affect CCE-
FT stimulated adenylate cyclase activity; when associated with
FT Q-814 and A-818."
FT /evidence="ECO:0000269|PubMed:19158400"
FT MUTAGEN 1120
FT /note="S->A: Does not affect the stimulatoty effect of PKA
FT inhibitor on calcium-stimulated adenylate cyclase
FT activity."
FT /evidence="ECO:0000269|PubMed:22976297"
FT MUTAGEN 1196
FT /note="L->A: Consistently high basal adenylate cyclase
FT activity; when associated with A-1200. Does not affect
FT calmodulin binding; when associated with A-1200."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1197
FT /note="V->A: Does not affect calcium activated adenylate
FT cyclase; when associated with A-1198. Does not affect
FT calcium activated adenylate cyclase; when associated with
FT A-1198 and A-1202.Decreases calcium/calmodulin stimulated
FT adenylate cyclase activity; when associated with 49-A--A-
FT 51; 38-A--A-40; A-1198 and A-1202. Has an elevated basal
FT activity; when associated with A-1198. Has an elevated
FT basal activity; when associated with A-1198 and A-1202.
FT Does not affect calmodulin binding; when associated with A-
FT 1198. Does not affect calmodulin binding; when associated
FT with A-1198 and A-1202."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1197
FT /note="V->N: Does not affect calcium activated adenylate
FT cyclase. Significant high basal adenylate cyclase activity.
FT Significant high basal adenylate cyclase activity; when
FT associated with Q-1202."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1198
FT /note="Q->A: Does not affect calcium activated adenylate
FT cyclase; when associated with A-1197. Does not affect
FT calcium activated adenylate cyclase; when associated with
FT A-1197 and A-1202. Decreases calcium/calmodulin stimulated
FT adenylate cyclase activity; when associated with 49-A--A-
FT 51; 38-A--A-40; A-1197 and A-1202. Has an elevated basal
FT activity; when associated with A-1197. Has an elevated
FT basal activity; when associated with A-1197 and A-1202.
FT Does not affect calmodulin binding; when associated with A-
FT 1197. Does not affect calmodulin binding; when associated
FT with A-1197 and A-1202."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1198
FT /note="Q->K: Does not affect calcium activated adenylate
FT cyclase."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1199
FT /note="S->D: Increased CCE-stimulated adenylate cyclase
FT activity. Has a high basal activity."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1200
FT /note="L->A: Consistently high basal adenylate cyclase
FT activity; when associated with A-1196. Does not affect
FT calmodulin binding; when associated with A-1196."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1202
FT /note="R->A: Does not affect calcium activated adenylate
FT cyclase; when associated with A-1197 and A-1198. Decreases
FT calcium/calmodulin stimulated adenylate cyclase activity;
FT when associated with 49-A--A-51; 38-A--A-40; A-1197 and A-
FT 1198. Has an elevated basal activity; when associated with
FT A-1197 and A-1198. Does not affect calmodulin binding; when
FT associated with A-1197 and A-1198."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1202
FT /note="R->E: Does not affect calcium activated adenylate
FT cyclase; when associated with E-1204. Greatly diminishes
FT calmodulin binding; when associated with E-1204."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1202
FT /note="R->Q: Does not affect calcium activated adenylate
FT cyclase. Increases slightly basal adenylate cyclase
FT activity but not significantly, and retains an appreciable
FT calcium regulation. Significant high basal adenylate
FT cyclase activity; when associated with N-1197."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1204
FT /note="R->E: Does not affect calcium activated adenylate
FT cyclase; when associated with E-1202. Greatly diminishes
FT calmodulin binding; when associated with E-1202."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1206
FT /note="K->E: Does not affect calcium activated adenylate
FT cyclase. Does not affect calmodulin binding."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1208
FT /note="L->E: Does not affect calcium activated adenylate
FT cyclase; when associated with E-1209. Does not affect
FT calmodulin binding; when associated with E-1209."
FT /evidence="ECO:0000269|PubMed:19305019"
FT MUTAGEN 1209
FT /note="L->E: Does not affect calcium activated adenylate
FT cyclase; when associated with E-1208. Does not affect
FT calmodulin binding; when associated with E-1208."
FT /evidence="ECO:0000269|PubMed:19305019"
SQ SEQUENCE 1248 AA; 139823 MW; 0171A3CEED034961 CRC64;
MELSDVHCLS GSEELYTIHP TPPAADGGSG SRPQRLLWQT AVRHITEQRF IHGHRGGGGG
GSRKASNPAG SGPNHHAPQL SSDSVLPLYS LGSGERAHNT GGTKVFPERS GSGSASGSGG
GGDLGFLHLD CAPSNSDFFL NGGYSYRGVI FPTLRNSFKS RDLERLYQRY FLGQRRKSEV
VMNVLDVLTK LTLLVLHLSL ASAPMDPLKG ILLGFFTGIE VVICALVVVR KDTTSHTYLQ
YSGVVTWVAM TTQILAAGLG YGLLGDGIGY VLFTLFATYS MLPLPLTWAI LAGLGTSLLQ
VTLQVLIPRL AVFSINQVLA QVVLFMCMNT AGIFISYLSD RAQRQAFLET RRCVEARLRL
ETENQRQERL VLSVLPRFVV LEMINDMTNV EDEHLQHQFH RIYIHRYENV SILFADVKGF
TNLSTTLSAQ ELVRMLNELF ARFDRLAHEH HCLRIKILGD CYYCVSGLPE PRQDHAHCCV
EMGLSMIKTI RFVRSRTKHD VDMRIGIHSG SVLCGVLGLR KWQFDVWSWD VDIANKLESG
GIPGRIHISK ATLDCLSGDY NVEEGHGKER NEFLRKHNIE TYLIKQPEES LLSLPEDIVK
ESVSCSDRRN SGATFTEGSW SPELPFDNIV GKQNTLAALT RNSINLLPNH LAQALHVQSG
PEEINKRIEH TIDLRSGDKL RREHIKPFSL MFKDSSLEHK YSQMRDEVFK SNLVCAFIVL
LFITAIQSLL PSSRLMPMTI QFSILIMLHS ALVLITTAED YKCLPLILRK TCCWINETYL
ARNVIIFASI LINFLGAVIN ILWCDFDKSI PLKNLTFNSS AVFTDICSYP EYFVFTGVLA
MVTCAVFLRL NSVLKLAVLL IMIAIYALLT ETIYAGLFLS YDNLNHSGED FLGTKEASLL
LMAMFLLAVF YHGQQLEYTA RLDFLWRVQA KEEINEMKDL REHNENMLRN ILPGHVARHF
LEKDRDNEEL YSQSYDAVGV MFASIPGFAD FYSQTEMNNQ GVECLRLLNE IIADFDELLG
EDRFQDIEKI KTIGSTYMAV SGLSPEKQQC EDKWGHLCAL ADFSLALTES IQEINKHSFN
NFELRIGISH GSVVAGVIGA KKPQYDIWGK TVNLASRMDS TGVSGRIQVP EETYLILKDQ
GFAFDYRGEI YVKGISEQEG KIKTYFLLGR VQPNPFILPP RRLPGQYSLA AVVLGLVQSL
NRQRQKQLLN ENSNSGIIKS HYNRRTLLTP SGPEPGAQAE GTDKSDLP
