id: MODULE:camp_pka_signal_transduction title: cAMP/PKA signal transduction — adenylyl cyclase cAMP production, PKA holoenzyme activation, AKAP anchoring and PDE termination; ADCY1-10, PRKAR1A/1B/2A/2B, PRKACA/B/G, AKAP1/5/6/7/10/12, EZR, PDE1-4/7/8/10/11 description: >- The cAMP/PKA cassette is the intracellular core shared by every Gs-coupled receptor and by bicarbonate/calcium sensing through soluble adenylyl cyclase. Cyclic AMP is made from ATP by ten mammalian adenylyl cyclases. Nine (ADCY1-9) are polytopic plasma-membrane enzymes whose two cytoplasmic catalytic domains form the active site; they are stimulated by GTP-bound G alpha s and are grouped by how other inputs regulate them: calcium/calmodulin stimulates ADCY1, ADCY3 and ADCY8; G beta gamma conditionally stimulates ADCY2, ADCY4 and ADCY7; G alpha i and calcium inhibit ADCY5 and ADCY6; ADCY9 is insensitive to forskolin. The tenth, ADCY10 (soluble adenylyl cyclase), has no membrane spans, is not regulated by heterotrimeric G proteins and is activated by bicarbonate and calcium. cAMP acts mainly through cAMP-dependent protein kinase (PKA). The inactive PKA holoenzyme is a tetramer of a regulatory-subunit dimer (type I, RIalpha/RIbeta, PRKAR1A/PRKAR1B; or type II, RIIalpha/RIIbeta, PRKAR2A/PRKAR2B) holding two catalytic subunits (Calpha, Cbeta, Cgamma; PRKACA, PRKACB, PRKACG) with a pseudosubstrate or substrate-like inhibitory segment in each active site. Each regulatory subunit has two cAMP-binding domains, and type I binds cAMP with higher affinity than type II. Binding of four cAMP molecules releases the catalytic subunits, which phosphorylate serine and threonine residues in R-R-X-S/T motifs of cytoplasmic and nuclear substrates. Where in the cell this happens is set by A-kinase anchoring proteins (AKAPs), which bind the docking/dimerisation domain of the regulatory dimer through an amphipathic helix, mostly that of type II PKA, and assemble PKA with substrates, phosphatases, phosphodiesterases and sometimes adenylyl cyclases at the plasma membrane, mitochondria, the perinuclear membrane and other sites. The signal is ended by cyclic-nucleotide phosphodiesterases (PDEs), the only enzymes that hydrolyse cAMP to 5'-AMP. PDE4, PDE7 and PDE8 are cAMP-specific, whereas PDE1, PDE2, PDE3, PDE10 and PDE11 hydrolyse both cAMP and cGMP and are regulated by calcium/calmodulin (PDE1) or by cGMP (stimulation of PDE2, inhibition of PDE3). PDEs tethered to AKAP complexes shape local cAMP microdomains, and PKA phosphorylation of some PDE4 isoforms provides negative feedback. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000543 title: protein kinase A (PKA) signaling pathway statement: >- The module boundary follows the RGD Pathway Ontology term and its diagram, which draws Gnas (linked to GPCRs upstream of PKA) acting on the AC members, ATP to cAMP, cAMP activating the Pka complex, Pdes negatively affecting cAMP, an Akaps member node, and the Pka complex positively affecting downstream outcomes (gene expression, metabolism, ion channels, exocytosis, cytoskeleton dynamics). The upstream receptor/Gs step is drawn as a link to the subpathway PW:0000227. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000543.yaml). - source_id: GO:0141156 title: cAMP/PKA signal transduction statement: >- The GO process mapped to PW:0000543 (skos:closeMatch, curated in projects/RGD_PATHWAY_ONTOLOGY/data/pw_go_curated.sssom.yaml): an intracellular signalling cassette that starts with cAMP production by transmembrane or soluble adenylate cyclase, activates PKA and ends with activation of downstream effectors. - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml statement: >- The RGD record text describes the holoenzyme composition and cAMP-induced dissociation used for the PKA parts. supporting_text: In the inactive state, the holoenzyme consists of two catalytic subunits (C) bound noncovalently to a regulatory dimer (RI or RII). - source_id: PMID:14715913 statement: >- Review framing the cassette as adenylyl cyclase production and PDE degradation of cAMP, distinct PKA isozymes, and AKAP targeting of PKA with its terminators. supporting_text: cAMP microdomains are shaped by adenylyl cyclases that form cAMP as well as phosphodiesterases that degrade cAMP. - source_id: PMID:19319965 statement: >- Review of AKAP biology used for the anchoring part: most AKAPs bind the type II holoenzyme, some are dual specificity. supporting_text: The majority of known AKAPs bind specifically to the RII holoenzyme. - source_id: PMID:17376027 statement: >- Review of cyclic nucleotide phosphodiesterases as essential components of cyclic-nucleotide signalling and of subcellular signalling compartments. supporting_text: the role of PDEs in generating subcellular signaling compartments notes: >- Derived from the RGD Pathway Ontology diagram PW:0000543 (protein kinase A (PKA) signaling pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. The PW record cites GO:0010737 protein kinase A signaling as its GO cross-reference; that term is obsolete (go-basic 2026-07-26) with consider pointers to GO:0007189 and GO:0141156. The project's curated SSSOM mapping uses GO:0141156 cAMP/PKA signal transduction (skos:closeMatch), which is the module concept here. The related obsolete GO:0019933 cAMP-mediated signaling points to the same two terms. RGD curates 50 human genes to PW:0000543: ADCY1-10; AKAP1, AKAP3-14 and PALM2AKAP2; EZR; CRHR2 and GLP1R; PDE1A/B/C, PDE2A, PDE3A/B, PDE4A-D, PDE7A/B, PDE8A/B, PDE10A, PDE11A; PRKACA/B/G; PRKAR1A/1B/2A/2B. Forty-four of them are modelled as participants or representative members below; the rest are discussed here. Boundary decisions. (1) This is the intracellular cassette, not a receptor pathway. modules/gpcr_camp_pka_signaling.yaml already models a compact five-gene receptor -> Gs -> ADCY5 -> PRKACA -> CREB1 chain (GO:0007188). It is not edited and not duplicated. Its receptor/Gs node is included here as an optional upstream part by module_ref (gpcr_camp_pka_signaling#gs_gpcr_activation). It is optional because ADCY10 makes cAMP without any receptor or G protein, and because Gi, Gq-calcium and G beta gamma inputs also tune the transmembrane cyclases. This module is the detailed expansion of that module's adenylyl cyclase and PKA nodes. The Gs hormone modules crh_receptor_signaling, beta_adrenergic_signaling, pth_receptor_signaling and glucagon_receptor_signaling still refer to the compact module's adenylyl_cyclase_activation and pka_creb_output parts, which also carry the CREB transcription step this module leaves out; moving them onto this module is pending. CRHR2 and GLP1R, which RGD lists, are Gs-coupled receptors that feed the cassette. They are upstream context, belong to receptor-specific modules (as the dopamine, vasopressin and acetylcholine modules do for their receptors) and are not modelled. RGD's subpathway PW:0000227 (Galphas signalling) is mentioned only here and is not an evidence source_id. CREB and the other PKA substrates drawn by RGD as outcomes (gene expression, metabolism, ion channels, exocytosis) are out of scope. Under the CLAUDE.md substrate-vs-participant rule, a PKA substrate does none of the work of the cassette, even though GO:0141156's definition ends at effector activation and CREB1, ATF1 and CREM carry the term in GOA. (2) cAMP production is a variant set on the axis of AC regulatory class, selection ONE_OR_MORE because most tissues express several isoforms (RGD: "Most tissues express more than one AC"). The grouping (Ca2+/CaM-stimulated AC1/3/8; G beta gamma-conditional AC2/4/7; Gi/Ca2+- inhibited AC5/6; forskolin-insensitive AC9; soluble AC10) is the standard classification. Of these, the calcium/calmodulin activation of AC1/AC8 and the calcium inhibition of AC5/AC6 are quoted from PMID:11264454. The G beta gamma class is stated from general knowledge, without a cached quote. All variants use adenylate cyclase activity GO:0004016, which is experimental (EXP/IDA/IMP) for ADCY2, ADCY5, ADCY6, ADCY7, ADCY9 and ADCY10. ADCY1, ADCY3, ADCY4 and ADCY8 carry it only by IBA/ISS/TAS/IEA. The calcium/calmodulin class could use the child GO:0008294 calcium- and calmodulin-responsive adenylate cyclase activity, but it is only ISS/NAS/TAS on ADCY1 and ADCY8 and was not used. (3) GO:0141156 placement and the comparator check. In human GOA (QuickGO, 2026-10), GO:0141156 is carried by 16 gene products. Most are effectors (CREB1, ATF1, CREM, CREBBP) or receptor/ligand context (EDN1, EDNRA, GHRHR). The anchors EZR (IMP), AKAP12 (IEA) and AKAP6 (ISS) also carry it. No adenylyl cyclase, PKA subunit or PDE does. GO:0141156 is a recent term, and its definition names adenylate cyclase cAMP production and PKA activation as the cassette's steps. The cyclases, the regulatory subunits and the catalytic subunits each do one of those steps, so the absence reads as term recency rather than a convention against annotating the enzymes. The term is therefore placed on the AC, PKA-R, PKA-C and AKAP annotons, matching the AKAP12 gene review, whose core anchoring and scaffolding functions are directly involved in GO:0141156. PDEs end the signal and are given cAMP catabolic process GO:0006198, the process they catalyse, not GO:0141156. The regulation term GO:0141162 negative regulation of cAMP/PKA signal transduction would also be defensible for PDEs, but no PDE carries it and it is not asserted. (4) PKA holoenzyme. The regulatory subunits are a variant set on the axis of holoenzyme type (type I RIalpha/RIbeta; type II RIIalpha/RIIbeta). All four use cAMP-dependent protein kinase regulator activity GO:0008603 (IDA on all four; also GO:0004862 inhibitor activity IDA), and cAMP binding is in the role text. The catalytic subunits are a separate variant set (selection ONE_OR_MORE). PRKACA and PRKACB use cAMP-dependent protein kinase activity GO:0004691 (IDA). PRKACG, a testis-expressed retrogene, has GO:0004691 only by IBA/IEA/TAS; its only experimental MF row is potassium channel inhibitor activity (EXP). The holoenzyme is not drawn as a single complex annoton because the active, released catalytic subunit is a monomer outside GO:0005952; the complex term is used for context in the regulatory annotons' role text instead. (5) AKAP anchoring is an optional part (PKA is catalytically competent without anchoring, and type I PKA is largely cytosolic). It is a variant set on the axis of anchoring compartment, selection ZERO_OR_MORE, naming the AKAPs whose anchoring role is supported by cached evidence: AKAP5 (AKAP79/150) and AKAP12 (gravin) and AKAP7 (AKAP18) at the plasma membrane; AKAP1 (D-AKAP1) and AKAP10 (D-AKAP2) at mitochondria; AKAP6 (mAKAP) at the perinuclear membrane; and EZR at membrane rafts. EZR is included. It is an ERM-family actin-membrane linker, not an AKAP by family, but it has a documented AKAP activity: it is the AKAP that targets type I PKA to T-cell lipid rafts (PMID:17911601), and GOA gives it IPI RI- and RII-binding rows and an IMP row for GO:0141156. MF on AKAP annotons is protein kinase A regulatory subunit binding GO:0034237, the AKAP7/AKAP10/AKAP12 gene-review core function and an experimental row for AKAP1, AKAP5, AKAP9 and AKAP14. AKAP6, AKAP7 and AKAP10 have only the parent GO:0051018 protein kinase A binding (IPI/IDA) in GOA, and EZR has GO:0034237 by IPI. AKAP3 and AKAP4 (sperm fibrous sheath), AKAP8 (AKAP95, nuclear matrix), AKAP9 (yotiao/AKAP450, centrosome/Golgi and KCNQ1), AKAP11 (AKAP220), AKAP13 (AKAP-Lbc, a Rho GEF), AKAP14 (AKAP28, cilia) and PALM2AKAP2 (AKAP2/AKAP-KL) are family members on the RGD list that are not named. They anchor PKA in specialised compartments that were not separately evidenced here. Note that PALM2AKAP2 (AKAP2) is a different gene from D-AKAP2, which is AKAP10. (6) Termination is a variant set on the axis of substrate selectivity (cAMP-specific vs dual cAMP/cGMP), selection ONE_OR_MORE, with one family annoton per PDE family. The cGMP-specific families (PDE5, PDE6, PDE9) are excluded, matching RGD's gene list. MFs follow the experimental rows: cAMP-specific PDE4/7/8 use 3',5'-cyclic-AMP phosphodiesterase activity GO:0004115 (IDA for PDE4A-D, PDE7A, PDE7B; IMP for PDE8A and PDE8B). PDE1 uses calmodulin-activated dual specificity GO:0004117 (IDA for PDE1A-C). PDE2 uses cGMP-stimulated GO:0004118 (IDA). PDE3 uses cGMP-inhibited GO:0004119 (IDA for PDE3A; PDE3B has only GO:0004114 EXP and GO:0004115 IDA). PDE10 and PDE11 use GO:0004115 (EXP), with their cGMP activity GO:0047555 (EXP) noted in the role text. (7) PKA feedback on PDE4 (PDE4D3 phosphorylation within the mAKAP complex, PMID:16177794) and AKAP tethering of AC5/6 (AKAP79) and of PDE4D (gravin, mAKAP) are recorded as connections and role text, not as separate parts. EPAC (RAPGEF3/4) and the cyclic-nucleotide-gated channels, the other cAMP effectors, are not in RGD's list and are out of scope. PKI (PKIA/B/G) inhibitors are not modelled. GO-CAM coverage. The project's lead model gomodel:693b3c0900000157 (GPR161 negative regulation of smoothened signalling via GLI3 processing) has ADCY3 adenylate cyclase activity, PRKAR1A cAMP-dependent protein kinase regulator activity and PRKACA cAMP-dependent protein kinase activity. It is linked at the module root and on those annotons. Other links: ADCY1 (gomodel:59dc728000000351), ADCY6 (gomodel:65288b2200000062, one of 123 ADCY6 activities in the index), ADCY10 (gomodel:680ad14200002972), PRKACA and PRKACB (gomodel:646ff70100003362, PKA phosphorylation of RPTOR), and AKAP5 (gomodel:62f58d8800004747). No GO-CAM in gocams/index.tsv covers ADCY2, ADCY4, ADCY5, ADCY7-9, PRKACG, PRKAR1B, PRKAR2A, PRKAR2B, any PDE, or AKAP1/6/7/10/12/EZR. Gene reviews exist only for AKAP7, AKAP10 and AKAP12. Their core functions were used. PANTHER family ids and PTNs are deliberately not asserted. Possible upstream issues noticed. (a) ADCY10 (soluble AC, insensitive to heterotrimeric G proteins per PMID:12609998) is drawn in gomodel:680ad14200002972 (GPR35 via G-alpha-i, inhibiting adenylate cyclase), so a Gi-inhibition context is attached to sAC. (b) PDE10A (UniProt name "cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A") and PDE11A carry GO:0004118 cGMP-stimulated cyclic-nucleotide phosphodiesterase activity by IDA from a single shared reference (the same paper also supports the PDE2A row). This sits uneasily with PDE2A being the canonical cGMP-stimulated PDE, but the paper was not read and the rows are not judged here. (c) The PW record's own GO cross-reference GO:0010737 is obsolete. module: id: camp_pka_signal_transduction label: cAMP/PKA signal transduction module_type: SIGNALING_PATHWAY concepts: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction description: >- The GO intracellular signalling cassette mapped to PW:0000543: adenylate cyclase cAMP production, PKA activation and effector phosphorylation. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol gocam_associations: - model: gomodel:693b3c0900000157 title: GPR161 acts as a negative regulator of smoothened pathway by promoting protein processing of GLI3 into transcription repressor GLI3R (Human). description: >- Project lead model. GPR161 -> GNAS -> ADCY3 adenylate cyclase activity -> PRKAR1A regulator / PRKACA cAMP-dependent protein kinase activity, with PKA acting on GLI3 processing. parts: - order: 1 optional: true role: receptor activation of Gs (upstream input) node: id: camp_upstream_gs_input label: Gs-coupled receptor activates G alpha s (shared upstream input) description: >- Included by reference to the receptor/Gs node of the compact GPCR-cAMP-PKA module. Optional because soluble adenylyl cyclase needs no receptor and because other G-protein and calcium inputs also regulate the transmembrane cyclases. Receptors on the RGD list (CRHR2, GLP1R) belong here, not in the cassette. module_ref: gpcr_camp_pka_signaling#gs_gpcr_activation - order: 2 role: cAMP synthesis from ATP by adenylyl cyclase node: id: camp_production label: Adenylyl cyclase production of cAMP module_type: REACTION description: >- Adenylyl cyclases convert ATP to cAMP and pyrophosphate. The nine transmembrane isoforms are stimulated by G alpha s and differ in how calcium, G beta gamma and G alpha i regulate them. The soluble isoform responds to bicarbonate and calcium. variant_sets: - id: adenylyl_cyclase_class label: Adenylyl cyclase regulatory class axis: regulatory class of the adenylyl cyclase isoform selection: ONE_OR_MORE notes: >- Most tissues express several isoforms; the classes share the C1/C2 catalytic mechanism and differ in regulation. evidence: - source_id: PMID:18948702 statement: Nine membrane-bound G protein-regulated AC isoforms plus a tenth that lacks membrane spans. supporting_text: Nine hormone-sensitive, membrane-bound AC isoforms have been identified in addition to a tenth isoform that lacks membrane spans and more closely resembles the cyanobacterial AC enzymes. - source_id: PMID:11264454 statement: Calcium/calmodulin activates AC1 and AC8; calcium inhibits AC5 and AC6. supporting_text: emphasizing the role of calcium/calmodulin in activating AC1 and AC8 in the central nervous system, the potential inhibitory effect of calcium on AC5 and AC6 variants: - id: ac_calcium_calmodulin_stimulated label: Calcium/calmodulin-stimulated transmembrane adenylyl cyclases (ADCY1, ADCY3, ADCY8) module_type: REACTION annotons: - id: adcy_group1 label: Ca2+/calmodulin-stimulated adenylyl cyclase participant: selector_type: FAMILY family: preferred_term: Ca2+/calmodulin-stimulated adenylyl cyclases (ADCY1, ADCY3, ADCY8) representative_members: - preferred_term: ADCY1 term: id: UniProtKB:Q08828 label: Adenylate cyclase type 1 - preferred_term: ADCY3 term: id: UniProtKB:O60266 label: Adenylate cyclase type 3 - preferred_term: ADCY8 term: id: UniProtKB:P40145 label: Adenylate cyclase type 8 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: cAMP biosynthetic process term: id: GO:0006171 label: cAMP biosynthetic process - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Neuronal and olfactory (ADCY3, ciliary membrane) cyclases that couple calcium entry to cAMP. GO:0004016 is IBA/ISS/TAS only for these three. evidence: - source_id: PMID:11264454 statement: Calcium/calmodulin activates AC1 and AC8. supporting_text: emphasizing the role of calcium/calmodulin in activating AC1 and AC8 in the central nervous system gocam_associations: - model: gomodel:693b3c0900000157 activity: gomodel:693b3c0900000157/693b3c0900000233 title: GPR161 acts as a negative regulator of smoothened pathway by promoting protein processing of GLI3 into transcription repressor GLI3R (Human). description: ADCY3 adenylate cyclase activity (GO:0004016) in the non-motile cilium membrane, downstream of GPR161/GNAS. - model: gomodel:59dc728000000351 activity: gomodel:59dc728000000351/59dc728000000362 title: GPCR - AC activating description: ADCY1 adenylate cyclase activity (GO:0004016) part of cAMP biosynthetic process. - id: ac_gbetagamma_conditional label: G beta gamma-conditional transmembrane adenylyl cyclases (ADCY2, ADCY4, ADCY7) module_type: REACTION annotons: - id: adcy_group2 label: G beta gamma-conditional adenylyl cyclase participant: selector_type: FAMILY family: preferred_term: G beta gamma-conditional adenylyl cyclases (ADCY2, ADCY4, ADCY7) representative_members: - preferred_term: ADCY2 term: id: UniProtKB:Q08462 label: Adenylate cyclase type 2 - preferred_term: ADCY4 term: id: UniProtKB:Q8NFM4 label: Adenylate cyclase type 4 - preferred_term: ADCY7 term: id: UniProtKB:P51828 label: Adenylate cyclase type 7 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: cAMP biosynthetic process term: id: GO:0006171 label: cAMP biosynthetic process - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- GO:0004016 is EXP for ADCY2 and IDA/IMP for ADCY7; ADCY4 has it by IBA/ISS only. Raf kinase activation of AC2 and AC6 is isoform-selective. evidence: - source_id: PMID:15385642 statement: Source of the experimental adenylate cyclase activity rows for ADCY2 (EXP) and ADCY5 (IDA). - id: ac_gi_calcium_inhibited label: Gi- and calcium-inhibited transmembrane adenylyl cyclases (ADCY5, ADCY6) module_type: REACTION annotons: - id: adcy_group3 label: Gi/Ca2+-inhibited adenylyl cyclase participant: selector_type: FAMILY family: preferred_term: Gi/Ca2+-inhibited adenylyl cyclases (ADCY5, ADCY6) representative_members: - preferred_term: ADCY5 term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 - preferred_term: ADCY6 term: id: UniProtKB:O43306 label: Adenylate cyclase type 6 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: cAMP biosynthetic process term: id: GO:0006171 label: cAMP biosynthetic process - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Cardiac and striatal cyclases (ADCY5 is the effector in the compact GPCR-cAMP-PKA module); GO:0004016 is EXP/IDA/IMP for ADCY5 and EXP/IDA for ADCY6. AKAP79 tethers AC5/6 to anchored PKA. evidence: - source_id: PMID:11264454 statement: Calcium inhibits AC5 and AC6. supporting_text: the potential inhibitory effect of calcium on AC5 and AC6 gocam_associations: - model: gomodel:65288b2200000062 activity: gomodel:65288b2200000062/6796b94c00004100 title: GPR174 signaling pathway (Human) description: ADCY6 adenylate cyclase activity (GO:0004016) downstream of GPR174/GNAS, upstream of PRKACA. - id: ac_forskolin_insensitive label: Forskolin-insensitive transmembrane adenylyl cyclase (ADCY9) module_type: REACTION annotons: - id: adcy9_cyclase label: ADCY9 adenylyl cyclase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADCY9 term: id: UniProtKB:O60503 label: Adenylate cyclase type 9 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: cAMP biosynthetic process term: id: GO:0006171 label: cAMP biosynthetic process - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Broadly expressed Gs-stimulated cyclase; GO:0004016 is EXP/IDA in GOA. - id: ac_soluble label: Soluble, bicarbonate- and calcium-activated adenylyl cyclase (ADCY10) module_type: REACTION annotons: - id: adcy10_soluble_cyclase label: Soluble adenylyl cyclase (sAC) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADCY10 term: id: UniProtKB:Q96PN6 label: Adenylate cyclase type 10 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: cAMP biosynthetic process term: id: GO:0006171 label: cAMP biosynthetic process - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- G protein- and forskolin-insensitive cyclase activated by bicarbonate and calcium; GO:0004016 and bicarbonate binding are IDA. Also found in nucleus and mitochondria, so cytosol is the main but not the only site. evidence: - source_id: PMID:12609998 statement: sAC is insensitive to G proteins and forskolin and is regulated by bicarbonate; calcium and bicarbonate act synergistically. supporting_text: In contrast to transmembrane adenylyl cyclases, sAC is insensitive to heterotrimeric G protein regulation and forskolin stimulation and is uniquely modulated by bicarbonate ions. - source_id: PMID:15659711 statement: Human sAC is mainly cytoplasmic, with some nuclear and plasma-membrane labelling. supporting_text: Confocal immunofluorescence cytochemistry localized hsAC primarily in cytoplasm, but some labeling was observed in the nucleus and the plasma membrane. gocam_associations: - model: gomodel:680ad14200002972 activity: gomodel:680ad14200002972/680ad14200002974 title: GPR35-mediated signaling via G-alpha-i (inhibitory), inhibiting adenylate cyclase promotes cardioprotection during ischemia following activation by kynurenic acid (Human). description: >- ADCY10 adenylate cyclase activity (GO:0004016) in mitochondrion, in a Gi-inhibition model; sAC is G protein-insensitive (see notes). - order: 3 role: cAMP binding to PKA regulatory subunits releases the catalytic subunits node: id: pka_holoenzyme_activation label: cAMP-induced dissociation of the PKA holoenzyme module_type: REGULATORY_STEP description: >- The R2C2 holoenzyme (cAMP-dependent protein kinase complex, GO:0005952) is held inactive by the regulatory dimer. Binding of four cAMP molecules, two to each regulatory subunit, changes the regulatory subunits' conformation and releases the two catalytic monomers. variant_sets: - id: pka_holoenzyme_type label: PKA holoenzyme type axis: regulatory subunit class (type I RI or type II RII) selection: ONE_OR_MORE notes: >- Type I binds cAMP with higher affinity than type II; type II is the main AKAP-anchored form, type I is largely cytosolic but can be anchored by dual-specificity AKAPs and by ezrin. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml statement: RGD states two type I and two type II regulatory subunits in humans and the higher cAMP affinity of type I. supporting_text: Each regulatory subunit has two cAMP binding sites; type I has a higher affinity for cAMP than type II. variants: - id: pka_type_i label: Type I PKA (RIalpha, RIbeta) module_type: REGULATORY_STEP annotons: - id: prkar1_regulatory label: PKA type I regulatory subunits participant: selector_type: FAMILY family: preferred_term: PKA type I regulatory subunits (PRKAR1A, PRKAR1B) representative_members: - preferred_term: PRKAR1A term: id: UniProtKB:P10644 label: cAMP-dependent protein kinase type I-alpha regulatory subunit - preferred_term: PRKAR1B term: id: UniProtKB:P31321 label: cAMP-dependent protein kinase type I-beta regulatory subunit function: preferred_term: cAMP-dependent protein kinase regulator activity term: id: GO:0008603 label: cAMP-dependent protein kinase regulator activity processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Holds catalytic subunits inactive in the holoenzyme and releases them on cAMP binding; GO:0008603 and GO:0004862 are IDA for both, cAMP binding is IMP for PRKAR1A. evidence: - source_id: PMID:16214430 statement: The catalytic subunit binds the RIalpha regulatory subunit with subnanomolar affinity, and cAMP-binding domain A of RIalpha changes conformation in the complex. supporting_text: In addition, cAMP-binding domain A undergoes major conformational changes. gocam_associations: - model: gomodel:693b3c0900000157 activity: gomodel:693b3c0900000157/693b3c0900000323 title: GPR161 acts as a negative regulator of smoothened pathway by promoting protein processing of GLI3 into transcription repressor GLI3R (Human). description: PRKAR1A cAMP-dependent protein kinase regulator activity (GO:0008603) regulating PRKACA. - id: pka_type_ii label: Type II PKA (RIIalpha, RIIbeta) module_type: REGULATORY_STEP annotons: - id: prkar2_regulatory label: PKA type II regulatory subunits participant: selector_type: FAMILY family: preferred_term: PKA type II regulatory subunits (PRKAR2A, PRKAR2B) representative_members: - preferred_term: PRKAR2A term: id: UniProtKB:P13861 label: cAMP-dependent protein kinase type II-alpha regulatory subunit - preferred_term: PRKAR2B term: id: UniProtKB:P31323 label: cAMP-dependent protein kinase type II-beta regulatory subunit function: preferred_term: cAMP-dependent protein kinase regulator activity term: id: GO:0008603 label: cAMP-dependent protein kinase regulator activity processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Lower cAMP affinity than type I; the docking/dimerisation domain of the RII dimer is the main AKAP-binding site, so type II PKA is the anchored form. GO:0008603 and GO:0004862 are IDA for both. evidence: - source_id: PMID:19319965 statement: Most AKAPs bind the RII holoenzyme. supporting_text: The majority of known AKAPs bind specifically to the RII holoenzyme. - order: 4 role: released catalytic subunits phosphorylate PKA substrates node: id: pka_catalytic_activity label: PKA catalytic subunit phosphorylation of substrates module_type: REACTION description: >- Free catalytic subunits phosphorylate serine/threonine residues of cytoplasmic, membrane and nuclear substrates. Which substrates are reached is set largely by AKAP anchoring of the holoenzyme. variant_sets: - id: pka_catalytic_isoform label: PKA catalytic subunit isoform axis: catalytic subunit gene selection: ONE_OR_MORE notes: >- Calpha and Cbeta are widely co-expressed; Cgamma is a primate-specific testis-expressed retrogene (rodents have two catalytic subunits). evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml statement: RGD states three catalytic subunits in humans and two in rodents. supporting_text: rodents express only two catalytic subunits variants: - id: pka_c_alpha label: PKA C-alpha (PRKACA) module_type: REACTION annotons: - id: prkaca_kinase label: PKA catalytic subunit alpha participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRKACA term: id: UniProtKB:P17612 label: cAMP-dependent protein kinase catalytic subunit alpha function: preferred_term: cAMP-dependent protein kinase activity term: id: GO:0004691 label: cAMP-dependent protein kinase activity processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Principal catalytic subunit; GO:0004691 is IDA in GOA. Also nuclear after release. evidence: - source_id: PMID:16705181 statement: Source of an IDA cAMP-dependent protein kinase activity row for PRKACA (multisite PKA phosphorylation of a substrate). gocam_associations: - model: gomodel:693b3c0900000157 activity: gomodel:693b3c0900000157/693b3c0900000265 title: GPR161 acts as a negative regulator of smoothened pathway by promoting protein processing of GLI3 into transcription repressor GLI3R (Human). description: PRKACA cAMP-dependent protein kinase activity (GO:0004691) phosphorylating GLI3. - model: gomodel:646ff70100003362 activity: gomodel:646ff70100003362/646ff70100003440 title: Inhibition of the canonical mTORC1 signaling via phosphorylation of RPTOR by PKA (PRKACA and PRKACB) (Human) description: PRKACA GO:0004691 phosphorylating RPTOR. - id: pka_c_beta label: PKA C-beta (PRKACB) module_type: REACTION annotons: - id: prkacb_kinase label: PKA catalytic subunit beta participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRKACB term: id: UniProtKB:P22694 label: cAMP-dependent protein kinase catalytic subunit beta function: preferred_term: cAMP-dependent protein kinase activity term: id: GO:0004691 label: cAMP-dependent protein kinase activity processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Paralog of C-alpha; GO:0004691 is IDA in GOA. gocam_associations: - model: gomodel:646ff70100003362 activity: gomodel:646ff70100003362/646ff70100003448 title: Inhibition of the canonical mTORC1 signaling via phosphorylation of RPTOR by PKA (PRKACA and PRKACB) (Human) description: PRKACB GO:0004691 phosphorylating RPTOR. - id: pka_c_gamma label: PKA C-gamma (PRKACG) module_type: REACTION annotons: - id: prkacg_kinase label: PKA catalytic subunit gamma participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRKACG term: id: UniProtKB:P22612 label: cAMP-dependent protein kinase catalytic subunit gamma function: preferred_term: cAMP-dependent protein kinase activity term: id: GO:0004691 label: cAMP-dependent protein kinase activity processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction role_description: >- Testis-expressed retrogene. GO:0004691 is IBA/IEA/TAS only; no experimental kinase row exists in GOA. - order: 5 optional: true role: AKAP anchoring and compartmentalisation of PKA node: id: pka_akap_anchoring label: A-kinase anchoring proteins target PKA to subcellular sites module_type: REGULATORY_STEP description: >- AKAPs bind the docking/dimerisation domain of the PKA regulatory dimer through an amphipathic helix and position the holoenzyme near particular substrates, often together with cyclases, phosphodiesterases and phosphatases. Optional, because PKA is catalytically competent without anchoring. variant_sets: - id: akap_compartment label: AKAP anchoring compartment axis: subcellular compartment to which PKA is anchored selection: ZERO_OR_MORE notes: >- Only AKAPs with cached evidence for their anchoring role are named; the other RGD-listed AKAP family members are discussed in the module notes. evidence: - source_id: PMID:19319965 statement: Most AKAPs carry a recognisable R-subunit binding sequence; several are dual specificity. supporting_text: However, several dual specificity AKAPs, which bind to both PKA subtypes, have been identified. variants: - id: akap_plasma_membrane label: Plasma-membrane AKAPs (AKAP5, AKAP12, AKAP7) module_type: REGULATORY_STEP annotons: - id: akap5_anchor label: AKAP79/150 postsynaptic and membrane scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKAP5 (AKAP79) term: id: UniProtKB:P24588 label: A-kinase anchor protein 5 function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Scaffolds PKA, PKC and calcineurin at the postsynaptic membrane and tethers AC5/AC6; GO:0034237 is IDA/IPI, adenylate cyclase binding IPI. evidence: - source_id: PMID:19319965 statement: AKAP79 scaffolds PKA, PKC and PP2B at the postsynaptic membrane. supporting_text: This is accomplished by AKAP79 through scaffolding, targeting and regulation of the signaling molecules PKA, protein kinase C (PKC) and protein phosphatase 2B (PP2B, calcineurin) at the post-synaptic membrane - source_id: PMID:19319965 statement: AKAP79/150 also tethers adenylyl cyclase V/VI. supporting_text: Interestingly, AKAP79/150 can also tether adenylyl cyclase V/VI, thereby forming a protein configuration to regulate cAMP production. gocam_associations: - model: gomodel:62f58d8800004747 activity: gomodel:62f58d8800004747/62f58d8800004751 title: ZDHHC2 in regulation of long-term synaptic potentiation via AKAP5 (Human) description: AKAP5 molecular adaptor activity (GO:0060090) in postsynaptic neurotransmitter receptor cycle. - id: akap12_anchor label: Gravin subplasmalemmal PKA-PDE4D scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKAP12 (gravin) term: id: UniProtKB:Q02952 label: A-kinase anchor protein 12 function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Matches the AKAP12 gene-review core function (GO:0034237, directly involved in GO:0141156); gravin also assembles PDE4D and adenylyl cyclase in the same subplasmalemmal complex. evidence: - source_id: PMID:16642035 statement: Gravin organises a PKA-PDE4D complex that terminates subplasmalemmal cAMP signals. supporting_text: Co-immunoprecipitation confirmed that gravin maintains a signaling complex that includes PKA and PDE4D. - id: akap7_anchor label: AKAP18 lipid-anchored membrane AKAP participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKAP7 (AKAP18alpha/beta) term: id: UniProtKB:O43687 label: A-kinase anchor protein 7 isoforms alpha and beta function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Matches the AKAP7 gene-review core function (GO:0034237 at the plasma membrane); GOA has the parent GO:0051018 by IDA. Couples PKA to L-type calcium channels. evidence: - source_id: PMID:9545239 statement: AKAP18 targets PKA to the plasma membrane and couples it to the L-type calcium channel. supporting_text: We have cloned a low-molecular weight A-kinase Anchoring Protein, called AKAP18, which targets the cAMP-dependent protein kinase (PKA) to the plasma membrane, and permits functional coupling to the L-type calcium channel. - id: akap_mitochondrial label: Mitochondrial dual-specificity AKAPs (AKAP1, AKAP10) module_type: REGULATORY_STEP annotons: - id: akap1_anchor label: D-AKAP1 mitochondrial outer-membrane AKAP participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKAP1 (D-AKAP1) term: id: UniProtKB:Q92667 label: A-kinase anchor protein 1, mitochondrial function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: mitochondrial outer membrane term: id: GO:0005741 label: mitochondrial outer membrane role_description: >- Dual-specificity AKAP anchoring PKA on the mitochondrial surface; GO:0034237 is IPI in GOA. evidence: - source_id: PMID:19319965 statement: AKAP1 anchors RIIalpha-PKA on mitochondria. supporting_text: Results show that anchoring of RIIα-PKA on mitochondria through targeting by AKAP1 effectively prevents the holoenzyme from interfering with the maturation process once it is initiated. - id: akap10_anchor label: D-AKAP2 dual-specificity AKAP participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKAP10 (D-AKAP2) term: id: UniProtKB:O43572 label: A-kinase anchor protein 10, mitochondrial function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: mitochondrion term: id: GO:0005739 label: mitochondrion role_description: >- Matches the AKAP10 gene-review core function (GO:0034237; cytosol and mitochondrion). Binds both RI and RII. evidence: - source_id: PMID:19319965 statement: D-AKAP2 targets PKA to mitochondria. supporting_text: One function of D-AKAP2 is to target PKA to the mitochondria - id: akap_perinuclear label: Perinuclear-membrane AKAP (AKAP6, mAKAP) module_type: REGULATORY_STEP annotons: - id: akap6_anchor label: mAKAP perinuclear PKA-PDE4D3-EPAC1 scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKAP6 (mAKAP) term: id: UniProtKB:Q13023 label: A-kinase anchor protein 6 function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: nuclear envelope term: id: GO:0005635 label: nuclear envelope role_description: >- Muscle-specific AKAP assembling PKA with PDE4D3 and EPAC1 at the perinuclear membrane of cardiomyocytes; GOA has GO:0051018-family rows by IPI only. evidence: - source_id: PMID:16177794 statement: mAKAP maintains a cAMP-responsive complex of PKA, PDE4D3 and EPAC1. supporting_text: Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. - source_id: PMID:16177794 statement: mAKAP assembles PDE4D3 and PKA at the perinuclear membrane. supporting_text: In cardiomyocytes, mAKAP assembles a negative feedback loop containing PDE4D3 and PKA at the perinuclear membrane - id: akap_membrane_raft label: Membrane-raft type I PKA anchoring by ezrin (EZR) module_type: REGULATORY_STEP annotons: - id: ezr_anchor label: Ezrin as type I PKA anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: EZR (ezrin) term: id: UniProtKB:P15311 label: Ezrin function: preferred_term: protein kinase A regulatory subunit binding term: id: GO:0034237 label: protein kinase A regulatory subunit binding processes: - preferred_term: cAMP/PKA signal transduction term: id: GO:0141156 label: cAMP/PKA signal transduction locations: - preferred_term: membrane raft term: id: GO:0045121 label: membrane raft role_description: >- ERM-family actin-membrane linker with AKAP activity: targets type I PKA to T-cell lipid rafts next to its substrate Csk. GO:0034237 is IPI and GO:0141156 is IMP in GOA. evidence: - source_id: PMID:17911601 statement: Ezrin is the AKAP that targets type I PKA to lipid rafts in T cells. supporting_text: we identified Ezrin as the A-kinase anchoring protein that targets PKA type I to lipid rafts - order: 6 role: hydrolysis of cAMP to 5'-AMP terminates the signal node: id: camp_hydrolysis_termination label: Phosphodiesterase hydrolysis of cAMP module_type: REACTION description: >- Cyclic-nucleotide phosphodiesterases hydrolyse cAMP to 5'-AMP, setting the amplitude, duration and spatial extent of cAMP and so of PKA activity. Anchored PDEs (PDE4D with gravin or mAKAP) shape local microdomains. variant_sets: - id: pde_selectivity label: Phosphodiesterase substrate selectivity axis: substrate selectivity of the PDE family (cAMP-specific or dual cAMP/cGMP) selection: ONE_OR_MORE notes: >- cGMP-specific PDE5, PDE6 and PDE9 are not part of this cassette and are not modelled. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml statement: RGD describes PDEs as the only cyclic-nucleotide-degrading enzymes and groups the 11 families by selectivity. supporting_text: cAMP is hydrolyzed by phosphodiesterases (PDE), the only enzymes degrading cycling nucleotides. variants: - id: pde_camp_specific label: cAMP-specific phosphodiesterases (PDE4, PDE7, PDE8) module_type: REACTION annotons: - id: pde4_family label: PDE4 cAMP-specific phosphodiesterases participant: selector_type: FAMILY family: preferred_term: PDE4 family (PDE4A, PDE4B, PDE4C, PDE4D) representative_members: - preferred_term: PDE4A term: id: UniProtKB:P27815 label: 3',5'-cyclic-AMP phosphodiesterase 4A - preferred_term: PDE4B term: id: UniProtKB:Q07343 label: 3',5'-cyclic-AMP phosphodiesterase 4B - preferred_term: PDE4C term: id: UniProtKB:Q08493 label: 3',5'-cyclic-AMP phosphodiesterase 4C - preferred_term: PDE4D term: id: UniProtKB:Q08499 label: 3',5'-cyclic-AMP phosphodiesterase 4D function: preferred_term: 3',5'-cyclic-AMP phosphodiesterase activity term: id: GO:0004115 label: 3',5'-cyclic-AMP phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Main cAMP-terminating family in most cells; GO:0004115 is IDA for all four. PDE4D isoforms are tethered by gravin and mAKAP, and PKA phosphorylation of PDE4D3 enhances its activity (negative feedback). evidence: - source_id: PMID:16642035 statement: Gravin-associated PDE4D rapidly terminates subplasmalemmal cAMP. supporting_text: We propose that gravin-associated PDE4D isoforms provide a means to rapidly terminate subplasmalemmal cAMP signals with concomitant effects on localized ion channels or enzyme activities. - source_id: PMID:16177794 statement: Anchored PKA stimulates PDE4D3 to lower local cAMP. supporting_text: Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. - id: pde7_family label: PDE7 high-affinity cAMP-specific phosphodiesterases participant: selector_type: FAMILY family: preferred_term: PDE7 family (PDE7A, PDE7B) representative_members: - preferred_term: PDE7A term: id: UniProtKB:Q13946 label: High affinity 3',5'-cyclic-AMP phosphodiesterase 7A - preferred_term: PDE7B term: id: UniProtKB:Q9NP56 label: 3',5'-cyclic-AMP phosphodiesterase 7B function: preferred_term: 3',5'-cyclic-AMP phosphodiesterase activity term: id: GO:0004115 label: 3',5'-cyclic-AMP phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: GO:0004115 is IDA for PDE7A and PDE7B. - id: pde8_family label: PDE8 high-affinity, IBMX-insensitive cAMP-specific phosphodiesterases participant: selector_type: FAMILY family: preferred_term: PDE8 family (PDE8A, PDE8B) representative_members: - preferred_term: PDE8A term: id: UniProtKB:O60658 label: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A - preferred_term: PDE8B term: id: UniProtKB:O95263 label: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B function: preferred_term: 3',5'-cyclic-AMP phosphodiesterase activity term: id: GO:0004115 label: 3',5'-cyclic-AMP phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: >- GO:0004115 is IMP for PDE8A and EXP/IMP for PDE8B. A pool of PDE8A binds Raf-1 and controls cAMP inhibition of Raf-1 signalling. evidence: - source_id: PMID:23509299 statement: PDE8A binds Raf-1 and regulates the cAMP-Raf-1 cross-talk node. supporting_text: Here, we report that at least part of the PDE8A in the cell can bind tightly to Raf-1, regulate Raf-1 phosphorylation on S259, and, in so doing, regulate the cross-talk node whereby cAMP exerts an inhibitory effect on Raf-1 signaling - id: pde_dual_specificity label: Dual cAMP/cGMP phosphodiesterases (PDE1, PDE2, PDE3, PDE10, PDE11) module_type: REACTION annotons: - id: pde1_family label: PDE1 calcium/calmodulin-activated dual phosphodiesterases participant: selector_type: FAMILY family: preferred_term: PDE1 family (PDE1A, PDE1B, PDE1C) representative_members: - preferred_term: PDE1A term: id: UniProtKB:P54750 label: Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A - preferred_term: PDE1B term: id: UniProtKB:Q01064 label: Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B - preferred_term: PDE1C term: id: UniProtKB:Q14123 label: Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C function: preferred_term: calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity term: id: GO:0004117 label: calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: Couples calcium signals to cyclic-nucleotide breakdown; GO:0004117 is IDA for all three. - id: pde2_family label: PDE2A cGMP-stimulated phosphodiesterase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE2A term: id: UniProtKB:O00408 label: cGMP-dependent 3',5'-cyclic phosphodiesterase function: preferred_term: 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity term: id: GO:0004118 label: 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: >- cGMP binding to the GAF domains stimulates cAMP hydrolysis, linking cGMP rises to lower cAMP; GO:0004118 and GO:0004115 are IDA. - id: pde3_family label: PDE3 cGMP-inhibited phosphodiesterases participant: selector_type: FAMILY family: preferred_term: PDE3 family (PDE3A, PDE3B) representative_members: - preferred_term: PDE3A term: id: UniProtKB:Q14432 label: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A - preferred_term: PDE3B term: id: UniProtKB:Q13370 label: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B function: preferred_term: 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity term: id: GO:0004119 label: 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: >- cGMP competitively inhibits cAMP hydrolysis. GO:0004119 is IDA for PDE3A; PDE3B has GO:0004115 IDA and GO:0004114 EXP but no GO:0004119 row. PDE3A limits cAMP in Golgi-associated microdomains. evidence: - source_id: PMID:19332778 statement: PDE3A depletion lets cAMP accumulate in microdomains. supporting_text: We suggest that decreasing PDE3A allowed cAMP to accumulate in microdomains where its enzymatic activity limited cAMP concentration. - id: pde10_family label: PDE10A dual phosphodiesterase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE10A term: id: UniProtKB:Q9Y233 label: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A function: preferred_term: 3',5'-cyclic-AMP phosphodiesterase activity term: id: GO:0004115 label: 3',5'-cyclic-AMP phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: >- Striatal dual PDE; GO:0004115 and cGMP phosphodiesterase GO:0047555 are EXP in GOA. - id: pde11_family label: PDE11A dual phosphodiesterase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE11A term: id: UniProtKB:Q9HCR9 label: Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A function: preferred_term: 3',5'-cyclic-AMP phosphodiesterase activity term: id: GO:0004115 label: 3',5'-cyclic-AMP phosphodiesterase activity processes: - preferred_term: cAMP catabolic process term: id: GO:0006198 label: cAMP catabolic process role_description: GO:0004115 and GO:0047555 are EXP in GOA. connections: - source: camp_upstream_gs_input target: camp_production connection_type: POSITIVELY_REGULATES description: GTP-bound G alpha s stimulates the transmembrane adenylyl cyclases (not ADCY10). - source: camp_production target: pka_holoenzyme_activation connection_type: PROVIDES_INPUT_FOR description: cAMP made by adenylyl cyclase binds the regulatory subunits of the holoenzyme. - source: pka_holoenzyme_activation target: pka_catalytic_activity connection_type: POSITIVELY_REGULATES description: cAMP binding releases the catalytic subunits from regulatory-subunit inhibition. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml statement: RGD text describes release of catalytic monomers on cAMP binding. supporting_text: cAMP binding to the PKA complex leads to dissociation of the catalytic subunits from the holoenzyme. - source: pka_akap_anchoring target: pka_holoenzyme_activation connection_type: POSITIVELY_REGULATES description: AKAPs bind the regulatory dimer and place the holoenzyme next to its substrates and terminators. - source: camp_hydrolysis_termination target: pka_holoenzyme_activation connection_type: NEGATIVELY_REGULATES description: PDE hydrolysis of cAMP lowers the cAMP available to the regulatory subunits. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml statement: RGD draws Pdes negatively affecting cAMP. supporting_text: PDEs not only contribute to the regulation of cAMP concentration but also modulate the duration and extent of cAMP signaling, and thus of PKA. - source: pka_catalytic_activity target: camp_hydrolysis_termination connection_type: POSITIVELY_REGULATES description: PKA phosphorylation of PDE4D3 enhances cAMP hydrolysis (negative feedback). evidence: - source_id: PMID:16177794 statement: Anchored PKA stimulates PDE4D3 to reduce local cAMP. supporting_text: Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations knowledge_gaps: - gap_statement: >- Whether the testis-expressed catalytic subunit PRKACG has cAMP-dependent protein kinase activity and a role in the cassette in vivo is not established; no experimental kinase activity is recorded for it. status: OPEN gap_kind: - BIOLOGY significance: >- Determines whether the C-gamma variant is a functional implementation of the catalytic step or a retrogene of uncertain activity. provenance: - reference_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000543.yaml supporting_text: rodents express only two catalytic subunits