Adcy8
entrez
29241
canonical
uniprot
P40146
canonical
ensembl
ENSRNOG00000004890
resolver
ensp
ENSRNOP00000006789
resolver
ensp
ENSRNOP00000085627
resolver
ensp
ENSRNOP00000086009
resolver
enst
ENSRNOT00000096414
resolver
enst
ENSRNOT00000098906
resolver
genesymbol
Adcy8
resolver
uniprot
A0A8I6A3U3
resolver
uniprot
A0A8I6GDK4
resolver
uniprot_entry
A0A8I6A3U3_RAT
resolver
uniprot_entry
A0A8I6GDK4_RAT
resolver
uniprot_entry
ADCY8_RAT
resolver
activity_regulation
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:19305019, PubMed:8163524, PubMed:8557635). 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 (PubMed:11744699, PubMed:19158400, PubMed:19171672, PubMed:20410303, PubMed:22494970). 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 (PubMed:20410303). 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 (PubMed:24086669, PubMed:25381556). Activated via stimulation of the GLP1R (PubMed:25381556). Synergistically activated by calcium/calmodulin and GNAS (PubMed:13680124). Stimulated by forskolin (PubMed:13680124, PubMed:16186630). Inhibited by PKA directly bound to AKAP5 at membrane raft (PubMed:21771783, PubMed:22976297). 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 (PubMed:16186630). {ECO:0000269|PubMed:11744699, ECO:0000269|PubMed:13680124, ECO:0000269|PubMed:16186630, ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:19171672, ECO:0000269|PubMed:19305019, ECO:0000269|PubMed:20410303, ECO:0000269|PubMed:21771783, ECO:0000269|PubMed:22494970, ECO:0000269|PubMed:22976297, ECO:0000269|PubMed:24086669, ECO:0000269|PubMed:25381556, ECO:0000269|PubMed:8163524, ECO:0000269|PubMed:8557635}.
uniprot
proteins
amino_acid_sequence
MELSDVHCLSGSEELYTIHPTPPAADGGSGSRPQRLLWQTAVRHITEQRFIHGHRGGGGGGSRKASNPAGSGPNHHAPQLSSDSVLPLYSLGSGERAHNTGGTKVFPERSGSGSASGSGGGGDLGFLHLDCAPSNSDFFLNGGYSYRGVIFPTLRNSFKSRDLERLYQRYFLGQRRKSEVVMNVLDVLTKLTLLVLHLSLASAPMDPLKGILLGFFTGIEVVICALVVVRKDTTSHTYLQYSGVVTWVAMTTQILAAGLGYGLLGDGIGYVLFTLFATYSMLPLPLTWAILAGLGTSLLQVTLQVLIPRLAVFSINQVLAQVVLFMCMNTAGIFISYLSDRAQRQAFLETRRCVEARLRLETENQRQERLVLSVLPRFVVLEMINDMTNVEDEHLQHQFHRIYIHRYENVSILFADVKGFTNLSTTLSAQELVRMLNELFARFDRLAHEHHCLRIKILGDCYYCVSGLPEPRQDHAHCCVEMGLSMIKTIRFVRSRTKHDVDMRIGIHSGSVLCGVLGLRKWQFDVWSWDVDIANKLESGGIPGRIHISKATLDCLSGDYNVEEGHGKERNEFLRKHNIETYLIKQPEESLLSLPEDIVKESVSCSDRRNSGATFTEGSWSPELPFDNIVGKQNTLAALTRNSINLLPNHLAQALHVQSGPEEINKRIEHTIDLRSGDKLRREHIKPFSLMFKDSSLEHKYSQMRDEVFKSNLVCAFIVLLFITAIQSLLPSSRLMPMTIQFSILIMLHSALVLITTAEDYKCLPLILRKTCCWINETYLARNVIIFASILINFLGAVINILWCDFDKSIPLKNLTFNSSAVFTDICSYPEYFVFTGVLAMVTCAVFLRLNSVLKLAVLLIMIAIYALLTETIYAGLFLSYDNLNHSGEDFLGTKEASLLLMAMFLLAVFYHGQQLEYTARLDFLWRVQAKEEINEMKDLREHNENMLRNILPGHVARHFLEKDRDNEELYSQSYDAVGVMFASIPGFADFYSQTEMNNQGVECLRLLNEIIADFDELLGEDRFQDIEKIKTIGSTYMAVSGLSPEKQQCEDKWGHLCALADFSLALTESIQEINKHSFNNFELRIGISHGSVVAGVIGAKKPQYDIWGKTVNLASRMDSTGVSGRIQVPEETYLILKDQGFAFDYRGEIYVKGISEQEGKIKTYFLLGRVQPNPFILPPRRLPGQYSLAAVVLGLVQSLNRQRQKQLLNENSNSGIIKSHYNRRTLLTPSGPEPGAQAEGTDKSDLP
uniprot
proteins
ec_number
4.6.1.1
uniprot
proteins
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:13680124, PubMed:21046358, PubMed:22494970, PubMed:24086669, PubMed:25381556, PubMed:8163524). 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:8163524). 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:13680124, PubMed:21046358, PubMed:25381556). 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 (PubMed:16741924). {ECO:0000269|PubMed:13680124, ECO:0000269|PubMed:16741924, ECO:0000269|PubMed:21046358, ECO:0000269|PubMed:22494970, ECO:0000269|PubMed:24086669, ECO:0000269|PubMed:25381556, ECO:0000269|PubMed:8163524}.
uniprot
proteins
mass_dalton
139823
uniprot
proteins
mutagenesis
MUTAGEN 1..106; /note="Missing: Does not affect adenylate cyclase activity in response to calcium in vitro. Reduces adenylate cyclase activity in response to capacitative calcium entry (CCE). Reduces colocalization with actin. Does not improve the distribution of the actin cytoskeleton at the plasma membrane."; /evidence="ECO:0000269|PubMed:22399809"; MUTAGEN 38..40; /note="WQT->AAA: Does not interact with CALM1; when associated with 49-A--A-51. Interacts with PPP2CA; when associated with 49-A--A-51. Greatly reduces CCE-stimulated adenylate cyclase activity; when associated with 49-A--A-51. Does not affect caveolar localization; when associated with 49-A--A-51. Does not affect calcium/calmodulin stimulated adenylate cyclase activity; when associated with 49-A--A-51. Decreases calcium/calmodulin stimulated adenylate cyclase activity; when associated with 49-A--A-51; A-1197; A-1198 and A-1202."; /evidence="ECO:0000269|PubMed:11744699, ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19305019"; MUTAGEN 49..51; /note="RFI->AAA: Does not interact with CALM1; when associated with 38-A--A-40. Interacts with PPP2CA; when associated with 38-A--A-40. Greatly reduces CCE-stimulated adenylate cyclase activity; when associated with 38-A--A-40. Does not affect caveolar localization; when associated with 38-A--A-40. Does not affect calcium/calmodulin stimulated adenylate cyclase activity; when associated with 38-A--A-40. Decreases calcium/calmodulin stimulated adenylate cyclase activity; when associated with 38-A--A-40; A-1197; A-1198 and A-1202."; /evidence="ECO:0000269|PubMed:11744699, ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19305019"; MUTAGEN 66; /note="S->A: Decraeses significantly the stimulatoty effect of PKA inhibitor on calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 112; /note="S->A: Loses the stimulatoty effect of PKA inhibitor on calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 112; /note="S->D: Insensitive to the stimulatory effect of PKA inhibitor on calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 178; /note="S->A: Does not affect the stimulatoty effect of PKA inhibitor on calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 416; /note="D->N: Loses adenylate cyclase activity in response to calcium."; /evidence="ECO:0000269|PubMed:22399809"; MUTAGEN 432; /note="L->A: Does not affect dimerization; when associated with A-439. Dramatically reduces the levels of the N-glycosylated monomeric species; when associated with A-439. Loss of calcium- and calmodulin-responsive adenylate cyclase activity; when associated with A-439. Affects membrane raft localization; when associated with A-439."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 439; /note="L->A: Does not affect dimerization. Does not affect dimerization;when associated with A-432. Does not affect dimerization;when associated with A-446 and A-432. Does not affect dimerization;when associated with A-432; A-446 and A-453. Dramatically reduces the levels of the N-glycosylated monomeric species. Dramatically reduces the levels of the N-glycosylated monomeric species; when associated with A-432. Dramatically reduces the levels of the N-glycosylated monomeric species; when associated with A-446 and A-432. Dramatically reduces the levels of the N-glycosylated monomeric species; when associated with A-453; A-432 and A-446. Loss of calcium- and calmodulin-responsive adenylate cyclase activity. Loss of calcium- and calmodulin-responsive adenylate cyclase activity; when associated with A-432. Loss of calcium- and calmodulin-responsive adenylate cyclase activity; when associated with A-446 and A-432. Loss of calcium- and calmodulin-responsive adenylate cyclase activity; when associated with A-453; A-432 and A-446. Affects membrane raft localization. Affects membrane raft localization; when associated with A-432. Affects membrane raft localization; when associated with A-446 and A-432. Affects membrane raft localization; when associated with A-439; A-432 and A-446."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 446; /note="L->A: Does not affect dimerization; when associated with A-439 and A-432. Dramatically reduces the levels of the N-glycosylated monomeric species; when associated with A-439 and A-432. Loss of calcium- and calmodulin-responsive adenylate cyclase activity; when associated with A-439 and A-432. Affects membrane raft localization; when associated with A-439 and A-432."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 453; /note="L->A: Does not affect dimerization; when associated with A-439; A-432 and A-446. Dramatically reduces the levels of the N-glycosylated monomeric species; when associated with A-439; A-432 and A-446. Loss of calcium- and calmodulin-responsive adenylate cyclase activity; when associated with A-439; A-432 and A-446. Affects membrane raft localization; when associated with A-439; A-432 and A-446."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 611; /note="S->A: Does not affect the stimulatoty effect of PKA inhibitoron calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 814; /note="N->Q: Does not affect deglycosylation. Does not affect plasma membrane targeting; when associated with Q-818 and A-885. Affects membrane raft localization; when associated with Q-818 and A-885. Does not affect CCE-stimulated adenylate cyclase activity; when associated with Q-818 and A-885."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 818; /note="N->Q: Does not affect deglycosylation. Does not affect plasma membrane targeting; when associated with Q-814 and A-885. Affects membrane raft localization; when associated with Q-814 and A-885. Does not affect CCE-stimulated adenylate cyclase activity; when associated with Q-814 and A-885."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 852; /note="S->A: Does not affect the stimulatoty effect of PKA inhibitoron calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 885; /note="N->E: Does not affect deglycosylation. Does not affect plasma membrane targeting; when associated with Q-814 and A-818. Affects membrane raft localization; when associated with Q-814 and A-818. Does not affect CCE-stimulated adenylate cyclase activity; when associated with Q-814 and A-818."; /evidence="ECO:0000269|PubMed:19158400"; MUTAGEN 1120; /note="S->A: Does not affect the stimulatoty effect of PKA inhibitor on calcium-stimulated adenylate cyclase activity."; /evidence="ECO:0000269|PubMed:22976297"; MUTAGEN 1196; /note="L->A: Consistently high basal adenylate cyclase activity; when associated with A-1200. Does not affect calmodulin binding; when associated with A-1200."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1197; /note="V->A: Does not affect calcium activated adenylate cyclase; when associated with A-1198. Does not affect calcium activated adenylate cyclase; when associated with A-1198 and A-1202. Decreases calcium/calmodulin stimulated adenylate cyclase activity; when associated with 49-A--A-51; 38-A--A-40; A-1198 and A-1202. Has an elevated basal activity; when associated with A-1198. Has an elevated basal activity; when associated with A-1198 and A-1202. Does not affect calmodulin binding; when associated with A-1198. Does not affect calmodulin binding; when associated with A-1198 and A-1202."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1197; /note="V->N: Does not affect calcium activated adenylate cyclase. Significant high basal adenylate cyclase activity. Significant high basal adenylate cyclase activity; when associated with Q-1202."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1198; /note="Q->A: Does not affect calcium activated adenylate cyclase; when associated with A-1197. Does not affect calcium activated adenylate cyclase; when associated with A-1197 and A-1202. Decreases calcium/calmodulin stimulated adenylate cyclase activity; when associated with 49-A--A-51; 38-A--A-40; A-1197 and A-1202. Has an elevated basal activity; when associated with A-1197. Has an elevated basal activity; when associated with A-1197 and A-1202. Does not affect calmodulin binding; when associated with A-1197. Does not affect calmodulin binding; when associated with A-1197 and A-1202."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1198; /note="Q->K: Does not affect calcium activated adenylate cyclase."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1199; /note="S->D: Increased CCE-stimulated adenylate cyclase activity. Has a high basal activity."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1200; /note="L->A: Consistently high basal adenylate cyclase activity; when associated with A-1196. Does not affect calmodulin binding; when associated with A-1196."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1202; /note="R->A: Does not affect calcium activated adenylate cyclase; when associated with A-1197 and A-1198. Decreases calcium/calmodulin stimulated adenylate cyclase activity; when associated with 49-A--A-51; 38-A--A-40; A-1197 and A-1198. Has an elevated basal activity; when associated with A-1197 and A-1198. Does not affect calmodulin binding; when associated with A-1197 and A-1198."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1202; /note="R->E: Does not affect calcium activated adenylate cyclase; when associated with E-1204. Greatly diminishes calmodulin binding; when associated with E-1204."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1202; /note="R->Q: Does not affect calcium activated adenylate cyclase. Increases slightly basal adenylate cyclase activity but not significantly, and retains an appreciable calcium regulation. Significant high basal adenylate cyclase activity; when associated with N-1197."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1204; /note="R->E: Does not affect calcium activated adenylate cyclase; when associated with E-1202. Greatly diminishes calmodulin binding; when associated with E-1202."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1206; /note="K->E: Does not affect calcium activated adenylate cyclase. Does not affect calmodulin binding."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1208; /note="L->E: Does not affect calcium activated adenylate cyclase; when associated with E-1209. Does not affect calmodulin binding; when associated with E-1209."; /evidence="ECO:0000269|PubMed:19305019"; MUTAGEN 1209; /note="L->E: Does not affect calcium activated adenylate cyclase; when associated with E-1208. Does not affect calmodulin binding; when associated with E-1208."; /evidence="ECO:0000269|PubMed:19305019
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8. {ECO:0000269|PubMed:21771783, ECO:0000269|PubMed:22976297}.; PTM: [Isoform 1]: N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity. {ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:8557635}.; PTM: [Isoform 3]: N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity. {ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:8557635}.
uniprot
proteins
protein_family
Adenylyl cyclase class-4/guanylyl cyclase family
uniprot
proteins
pubmed
11744699
uniprot
proteins
pubmed
11856299
uniprot
proteins
pubmed
13680124
uniprot
proteins
pubmed
16186630
uniprot
proteins
pubmed
16258073
uniprot
proteins
pubmed
16741924
uniprot
proteins
pubmed
19158400
uniprot
proteins
pubmed
19171672
uniprot
proteins
pubmed
19305019
uniprot
proteins
pubmed
20410303
uniprot
proteins
pubmed
21046358
uniprot
proteins
pubmed
21771783
uniprot
proteins
pubmed
22399809
uniprot
proteins
pubmed
22494970
uniprot
proteins
pubmed
22673903
uniprot
proteins
pubmed
22976297
uniprot
proteins
pubmed
24086669
uniprot
proteins
pubmed
25381556
uniprot
proteins
pubmed
8163524
uniprot
proteins
pubmed
8557635
uniprot
proteins
sequence_length
1248
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19171672, ECO:0000269|PubMed:21046358, ECO:0000269|PubMed:8163524}; Multi-pass membrane protein. Cell projection, dendrite {ECO:0000269|PubMed:16258073}. Membrane raft {ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:19158400, ECO:0000269|PubMed:19171672, ECO:0000269|PubMed:22494970}. Membrane, coated pit {ECO:0000269|PubMed:19158400}. Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000269|PubMed:19158400}. Membrane, caveola {ECO:0000269|PubMed:11744699}. Basolateral cell membrane {ECO:0000250|UniProtKB:P97490}. Apical cell membrane {ECO:0000250|UniProtKB:P97490}. Synapse {ECO:0000250|UniProtKB:P97490}. Cell projection, dendrite {ECO:0000250|UniProtKB:P97490}. Cell projection, axon {ECO:0000250|UniProtKB:P97490}. Presynaptic cell membrane {ECO:0000250|UniProtKB:P97490}. Postsynaptic density {ECO:0000250|UniProtKB:P97490}. Note=Localized to dendritic arbors (By similarity). Monomeric N-glycosylated specieslocalized 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 (PubMed:19158400). {ECO:0000250|UniProtKB:P97490, ECO:0000269|PubMed:19158400}.
uniprot
proteins
transmembrane_region
TRANSMEM 180..200; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 209..229; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 244..264; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 271..291; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 293..313; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 318..338; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 713..733; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 735..755; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 784..804; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 828..848; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 858..878; /note="Helical"; /evidence="ECO:0000255"; TRANSMEM 891..911; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins