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

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.

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.