id: MODULE:dopamine_receptor_signaling title: Dopamine receptor signaling — D1-like Golf/Gs and D2-like Gi/o control of adenylyl cyclase, the cAMP/PKA/DARPP-32/PP1 switch, and GRK/arrestin/RGS termination in striatal neurons description: >- Dopamine signals through five G protein-coupled receptors split into two classes with opposite effects on adenylyl cyclase. The D1-like receptors (DRD1 and DRD5) couple through the stimulatory G alpha subunits — in the striatum chiefly the Golf variant GNAL rather than ubiquitous Gs — to activate adenylyl cyclase type 5 (ADCY5), raising cAMP and activating cAMP-dependent protein kinase (PKA). The D2-like receptors (DRD2, DRD3 and DRD4) couple through the inhibitory G alpha subunits GNAI2 and GNAO1 to inhibit ADCY5 and lower cAMP. The signal converges on a single bistable integrator, the phosphoprotein DARPP-32 (PPP1R1B). When PKA phosphorylates DARPP-32 at threonine 34 it becomes a potent inhibitor of protein phosphatase 1 (PP1, the PPP1CA/PPP1CB/PPP1CC catalytic subunits), amplifying phosphorylation of PP1 substrates downstream of D1 signalling. The switch is governed by a network of kinases and phosphatases acting on distinct residues: CDK5 phosphorylates threonine 75, converting DARPP-32 into a competitive inhibitor of PKA; a PKA-activated PP2A holoenzyme with the B56-delta regulatory subunit (PPP2R5D) and a Ca2+-activated PP2A holoenzyme with the PR72 subunit (PPP2R3A) dephosphorylate threonine 75; the Ca2+/calmodulin phosphatase calcineurin (PPP3CA/PPP3CB/PPP3CC) dephosphorylates threonine 34; and casein kinase 1 (CSNK1A1) phosphorylates serine 137 to protect phospho-threonine 34 from calcineurin. Receptor output is terminated by G protein-coupled receptor kinases (GRK2, GRK3, GRK5, GRK6), which phosphorylate agonist-occupied receptors so that beta-arrestins (ARRB1, ARRB2) uncouple them from G proteins and drive internalisation, and by regulators of G protein signalling, most prominently the striatal RGS9-2/G-beta-5/R7BP GAP complex (RGS9, GNB5, RGS7BP) that accelerates GTP hydrolysis on the D2-coupled G alpha subunits. Dopamine signalling also reaches the ERK cascade through DARPP-32-dependent control of the striatal tyrosine phosphatase STEP (PTPN5), and D2 receptors engage a G protein-independent arrestin arm in which ARRB2 scaffolds PP2A onto AKT. status: DRAFT scope: CONCRETE references: - id: PMID:21303898 title: The physiology, signaling, and pharmacology of dopamine receptors. findings: - statement: >- D1-like receptors couple to Gs/Golf and stimulate adenylyl cyclase while D2-like receptors couple to Gi/o and inhibit it, and dopamine receptors also act through G protein-independent arrestin mechanisms. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Comprehensive peer-reviewed review (Pharmacol Rev) used for the canonical class-specific coupling and the arrestin arm; PubMed-verified. - id: PMID:11238742 title: Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:12665504 title: Motor dysfunction in type 5 adenylyl cyclase-null mice. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:6087160 title: DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:10604473 title: Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:17301223 title: Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:17535922 title: The B''/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:7708705 title: "Dopamine- and cAMP-regulated phosphoprotein DARPP-32: phosphorylation of Ser-137 by casein kinase I inhibits dephosphorylation of Thr-34 by calcineurin." reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Establishes the CK1->Ser137 mechanism; the specific CK1 isoform assayed is not identified as CSNK1A1, so the gene-level assignment carries an isoform caveat recorded in the module notes. - id: PMID:12718862 title: Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:12818179 title: RGS9 modulates dopamine signaling in the basal ganglia. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:23857581 title: Macromolecular composition dictates receptor and G protein selectivity of regulator of G protein signaling (RGS) 7 and 9-2 protein complexes in living cells. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:19332565 title: Changes in striatal signaling induce remodeling of RGS complexes containing Gbeta5 and R7BP subunits. reference_review: relevance: MEDIUM correctness: VERIFIED - id: PMID:12483215 title: NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. reference_review: relevance: MEDIUM correctness: VERIFIED - id: PMID:15608059 title: Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:16051150 title: An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. reference_review: relevance: HIGH correctness: VERIFIED - id: PMID:17194762 title: D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. reference_review: relevance: LOW correctness: DISPUTED review_notes: >- Proposes a Gq-coupled D1-D2 heteromer; the claim is contested (see PMID:25560761) and the putative heteromer is deliberately kept out of the module core. - id: PMID:25560761 title: Evidence against dopamine D1/D2 receptor heteromers. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- In vitro and in vivo evidence against Gq coupling by D1/D2 heteromers; cited for the decision to exclude the heteromer arm. evidence: - source_id: PW:0000394 title: dopamine signaling pathway statement: >- The module boundary and its core gene products follow the RGD interactive diagram for this Pathway Ontology term. The diagram and its record text draw D1-like receptors (Drd1, Drd5) signalling via Gnal (the Golf variant) and D2-like receptors (Drd2, Drd3, Drd4) signalling via Galphai (Gnao1 or Gnai2) to promote or inhibit adenylyl cyclase (Adcy5), cAMP production and PKA signalling; PPP1R1B (Darpp-32) as the major PKA substrate whose Thr34 phosphorylation inhibits PP1 (Ppp1c), with Thr75 phosphorylation by Cdk5, PP2A and calcineurin dephosphorylation and casein kinase 1 serine phosphorylation; Ptpn5 (STEP) acting negatively on the Raf/Mek/Erk pathway downstream of Pp1; and termination by RGS proteins (acting on Gnai2, Gnal, Gnao1), GRK kinases and beta-arrestins (Arrb1, Arrb2), including the Arrb2/phosphoprotein phosphatase 2/Akt arm. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000394.yaml). - source_id: GO:0007212 title: G protein-coupled dopamine receptor signaling pathway statement: >- The module is grounded in GO G protein-coupled dopamine receptor signaling pathway, the relatedMatch GO mapping recorded for PW:0000394 in the project's module seeds. Its children adenylate cyclase-activating dopamine receptor signaling pathway (GO:0007191) and adenylate cyclase-inhibiting dopamine receptor signaling pathway (GO:0007195) correspond to the D1-like and D2-like arms of this module. - source_id: PMID:6087160 title: DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. statement: >- Establishes DARPP-32 as a phosphorylation-dependent inhibitor of protein phosphatase 1, the central effector step of the module. supporting_text: >- We report here that DARPP-32 inhibits protein phosphatase-1 at nanomolar concentrations. Moreover, like inhibitor-1, DARPP-32 is effective as an inhibitor in its phosphorylated but not its dephosphorylated form. - source_id: PMID:11238742 title: Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. statement: >- Genetic evidence that in the striatum the D1-adenylyl cyclase response runs through Golf (GNAL) rather than ubiquitous Gs, fixing GNAL as the D1-like transducer here. supporting_text: >- we demonstrate here the obligatory role of this protein in the adenylyl cyclase responses to dopamine and adenosine in the caudate putamen. - source_id: PMID:12665504 title: Motor dysfunction in type 5 adenylyl cyclase-null mice. statement: >- Genetic evidence that ADCY5 is the striatal cyclase integrating both the D1 stimulatory and D2 inhibitory inputs. supporting_text: >- D1 dopaminergic agonist-stimulated adenylyl cyclase activity was attenuated, and this was accompanied by a decrease in the expression of the D1 dopaminergic receptor and G(s)alpha. D2 dopaminergic agonist-mediated inhibition of adenylyl cyclase activity was also blunted. notes: >- Derived from the RGD Pathway Ontology diagram PW:0000394 through the RGD_PATHWAY_ONTOLOGY project. The RGD diagram and its long record text supplied the boundary, the two receptor classes and their opposite coupling, the cAMP/PKA/DARPP-32/PP1 core, the DARPP-32 phospho-switch, the STEP/ERK branch and the GRK/arrestin/RGS termination machinery. Molecular functions were taken from each protein's experimental GO annotations in QuickGO and the primary literature, verified against go-basic (releases/2026-07-26). Core versus regulation. The module core is the canonical cascade: D1-like receptors (DRD1 GO:0001588 IDA, DRD5 GO:0001588 IDA) -> Golf/Gs (GNAL GO:0003925) -> ADCY5 (GO:0004016 IDA/EXP) -> cAMP -> PKA catalytic subunits (PRKACA/PRKACB/PRKACG GO:0004691 IDA/IBA) -> DARPP-32 phospho-Thr34 (PPP1R1B GO:0004864 protein phosphatase inhibitor activity, IDA PMID:6087160) inhibiting PP1 (PPP1CA/PPP1CB/PPP1CC GO:0004722), and the opposing D2-like arm (DRD2/DRD3/DRD4 GO:0001591 IDA) -> Gi/o (GNAI2, GNAO1 GO:0003925) inhibiting ADCY5. Everything else is regulation: the DARPP-32 phospho-switch, GRK/arrestin desensitisation, the RGS GAP step, the STEP/ERK branch and the non-canonical arrestin-AKT arm. These are modelled as separate REGULATORY_STEP parts and linked with POSITIVELY_REGULATES/NEGATIVELY_REGULATES connections rather than folded into the core reaction chain. DARPP-32 as a participant, not a mere substrate. DARPP-32 is a PKA/CDK5 substrate, but it does the work of the step it is annotated to: phospho-Thr34-DARPP-32 is itself the active inhibitor of PP1 (GO:0004864, IDA PMID:6087160) and phospho-Thr75-DARPP-32 is itself the active inhibitor of PKA (PMID:10604473), so it is a legitimate functional participant and the hub of the switch, not a passive input. PP2A and calcineurin are modelled as holoenzyme complexes, because specificity for DARPP-32 is set by the regulatory subunit. B56-delta/PPP2R5D (GO:0019888, IDA) directs the cAMP/PKA-driven Thr75 dephosphorylation (PMID:17301223) and PR72/PPP2R3A (GO:0019888) directs the Ca2+-driven Thr75 dephosphorylation (PMID:17535922); the catalytic subunits PPP2CA/PPP2CB carry protein serine/threonine phosphatase activity (GO:0004722). Calcineurin (catalytic PPP3CA/PPP3CB/PPP3CC, GO:0033192 IDA) dephosphorylates Thr34. The regulatory subunits that are not in the RGD gene list (PP2A scaffold PPP2R1A, calcineurin B PPP3R1) are omitted; their absence is a deliberate scope choice, not a claim they are uninvolved. CSNK1A1/CK1 and Ser137. The RGD diagram lists CSNK1A1 among the DARPP-32 kinases. The Ser137 mechanism (phospho-Ser137 blocks Thr34 dephosphorylation by calcineurin) is shown in PMID:7708705 for casein kinase I, which did not resolve which CK1 gene product is responsible; the CSNK1A1-level assignment therefore rests on the RGD curation plus CSNK1A1's experimental protein serine/threonine kinase activity (GO:0004674 EXP/IDA), and the isoform caveat is flagged in a knowledge gap. RGS9-2/G-beta-5/R7BP. The striatal GAP for the D2-coupled G alpha subunits is the obligate RGS9-2 (RGS9 GO:0005096 GTPase activator activity, IMP/IBA) / G-beta-5 (GNB5 GO:0005096, IDA, the atypical beta subunit) / R7BP (RGS7BP, the palmitoylated membrane anchor) trimer (PMID:23857581, PMID:19332565). RGS7BP carries no GO molecular function (it is a scaffold/anchor), so it is a functionless active unit, kept visible because it sets the complex's localisation and stability. RGS2, RGS4 and RGS7 (GO:0005096) are the additional GAPs the RGD text names under "RGS in DA signaling" and are modelled as an alternative variant within the same termination part. STEP (PTPN5) and SRC. PTPN5/STEP is retained because it has a defined, directly supported role: it dephosphorylates and inactivates ERK (GO:0004725 protein tyrosine phosphatase activity, IBA/TAS; PMID:12483215, PMID:15608059), and DARPP-32/PP1 controls its phosphorylation state, so it is the mechanistic link from the cAMP/PP1 core to the ERK branch drawn on the RGD diagram. SRC is on RGD's wider human gene list but is not drawn on the diagram and has only a broad, indirect role (a ubiquitous tyrosine kinase implicated in D1/NMDA potentiation); it is excluded as peripheral rather than asserted with a dopamine-specific function it does not have in GOA. Non-canonical arrestin-AKT arm. The RGD record text states that Arrb2 in complex with Drd2 and PP2 inactivates PI3K/Akt and activates GSK3. This G protein-independent arm (PMID:16051150, GO:0160213 beta-arrestin-dependent dopamine receptor signaling pathway) is modelled as a regulatory part: ARRB2 (GO:0030674 protein-macromolecule adaptor activity, IDA) scaffolds PP2A (GO:0004722) onto AKT1, lowering AKT activity and disinhibiting GSK3B. AKT1 and GSK3B are not on the RGD curated gene-link list but are named in the RGD description and have completed gene reviews, so they are included as the targets of this arm. Deliberately outside the module. Dopamine biosynthesis (TH, DDC and partners; RGD subpathway PW:0000802) is upstream ligand supply, not receptor signalling, and is kept in modules/catecholamine_biosynthesis.yaml rather than duplicated (the human GO-CAM gomodel:69c59f8a00000117 models that step). This module is the concrete striatal instantiation of the generic Gs-coupled and Gi-coupled GPCR-cAMP motif in modules/gpcr_camp_pka_signaling.yaml; the Gq/PLC/calcium/PKC branch of dopamine signalling (proposed for a D1-D2 heteromer) is the generic motif in modules/gpcr_plc_calcium_pkc_signaling.yaml and is NOT included here, because the existence of a Gq-coupled D1/D2 heteromer is contested: PMID:17194762 reports it while PMID:25560761 was unable to detect Gq/G11 coupling to D1/D2 homomers or heteromers and challenges the complex in vivo. This is recorded as a knowledge gap rather than asserted. GO-CAM grounding. The curator-built human DRD1-DRD5 Gs and DRD2-DRD4 Gi/Go dopamine signalling models (gomodel:69c59f8a*) match this module's receptor and G protein activities and are linked under gocam_associations. Those models type the G protein with G protein activity (GO:0003925) and the cyclase with adenylate cyclase activity (GO:0004016); they use ADCY6 as the cyclase exemplar where this module uses the striatal ADCY5 named by the RGD diagram and PMID:12665504. The striatal DARPP-32 switch, the PP2A and calcineurin steps, and the RGS/GRK/arrestin termination machinery are not covered by any cached production GO-CAM, so those molecular functions were taken from QuickGO and the primary literature directly. No gene reviews exist for the receptors, G proteins, ADCY5, PKA, PP1, DARPP-32, GRKs, arrestins or RGS proteins; reviews exist for CDK5, PPP2CA, PPP2CB, PPP3CA, PPP3CB, AKT1 and GSK3B and were used for those molecular functions, except that AKT1 is given GO:0106310 protein serine kinase activity, the specific child of its review's GO:0004674, because the step modelled here is AKT's inhibitory serine phosphorylation of GSK3B. knowledge_gaps: - gap_statement: >- Whether a Gq/G11-coupled D1-D2 dopamine receptor heteromer exists at endogenous expression levels in vivo, and if so what fraction of striatal phospholipase C/calcium signalling it carries, is unresolved. boundary: >- The module models only the adenylyl-cyclase-coupled D1-like and D2-like arms; no Gq/PLC heteromer arm is asserted. gap_kind: - BIOLOGY status: OPEN significance: >- PMID:17194762 reports a Gq-coupled, calcium-mobilising D1-D2 heteromer, but PMID:25560761 could not detect Gq/G11 coupling and found D1 and D2 receptors segregated in vivo, so the arm cannot be committed to the core without resolution. resolution: >- Resolve with endogenous-level proximity and G protein-coupling assays in identified striatal neurons and with genetic dissection of SKF83959 responses. - gap_statement: >- Which casein kinase 1 gene product phosphorylates DARPP-32 at Ser-137 in striatal neurons has not been established at the gene level. boundary: >- CSNK1A1 is assigned the Ser137 kinase role from the RGD curation and its experimental kinase activity, but the biochemistry (PMID:7708705) was done with casein kinase I of unspecified isoform. gap_kind: - BIOLOGY status: OPEN significance: >- Determines whether CSNK1A1 specifically, or another CK1 isoform, gates calcineurin access to phospho-Thr34. resolution: >- Isoform-specific knockdown/knockout and in situ phosphosite measurement of DARPP-32 Ser137 in striatal neurons. module: id: dopamine_receptor_signaling label: Dopamine receptor signaling (striatal) module_type: SIGNALING_PATHWAY concepts: - preferred_term: G protein-coupled dopamine receptor signaling pathway term: id: GO:0007212 label: G protein-coupled dopamine receptor signaling pathway description: >- Dopamine binding to D1-like or D2-like GPCRs and the opposite modulation of adenylyl cyclase, cAMP and PKA, integrated on DARPP-32/PP1 and terminated by GRKs, arrestins and RGS proteins. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the pathway is conserved across mammals and the diagram is RGD's rat curation. cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: Receptors, G proteins and ADCY5 act at the (postsynaptic) plasma membrane. - preferred_term: cytosol term: id: GO:0005829 label: cytosol description: PKA, DARPP-32, PP1, PP2A, calcineurin and the kinases act in the cytosol. parts: - order: 1 role: D1-like receptor coupling to Golf and stimulation of adenylyl cyclase node: id: dopa_d1_golf label: D1-like dopamine receptors activate Golf module_type: REGULATORY_STEP description: >- Dopamine-occupied D1-like receptors (DRD1, DRD5) act as guanine nucleotide exchange factors for the stimulatory G alpha subunit, in the striatum chiefly the Golf variant GNAL, producing active G alpha-GTP that stimulates adenylyl cyclase. concepts: - preferred_term: adenylate cyclase-activating dopamine receptor signaling pathway term: id: GO:0007191 label: adenylate cyclase-activating dopamine receptor signaling pathway annotons: - id: gnal_golf label: Golf (GNAL) G protein activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAL (G alpha olf) term: id: UniProtKB:P38405 label: Guanine nucleotide-binding protein G(olf) subunit alpha function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity targets: - preferred_term: ADCY5 (adenylyl cyclase 5) term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 processes: - preferred_term: adenylate cyclase-activating dopamine receptor signaling pathway term: id: GO:0007191 label: adenylate cyclase-activating dopamine receptor signaling pathway locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- The striatal stimulatory G alpha; GNAL (Golf), not ubiquitous Gs, carries the D1-adenylyl cyclase response in the caudate-putamen and nucleus accumbens. evidence: - source_id: PMID:11238742 statement: >- Galpha(olf)-deficient mice lose the adenylyl cyclase response to dopamine in the caudate putamen. supporting_text: >- we demonstrate here the obligatory role of this protein in the adenylyl cyclase responses to dopamine and adenosine in the caudate putamen. variant_sets: - id: d1_like_receptors label: D1-like dopamine receptors axis: receptor paralog selection: ONE_OR_MORE notes: >- DRD1 and DRD5 are the two D1-like receptors; both couple to Gs/Golf and stimulate adenylyl cyclase. DRD1 is the dominant striatal D1-like receptor and DRD5 is more restricted, so either (or both) satisfies this step. variants: - id: drd1_variant label: Dopamine receptor D1 (DRD1) module_type: REGULATORY_STEP annotons: - id: drd1_receptor label: DRD1 dopamine receptor coupled via Gs participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DRD1 term: id: UniProtKB:P21728 label: Dopamine receptor D1 function: preferred_term: dopamine neurotransmitter receptor activity, coupled via Gs term: id: GO:0001588 label: dopamine neurotransmitter receptor activity, coupled via Gs processes: - preferred_term: adenylate cyclase-activating dopamine receptor signaling pathway term: id: GO:0007191 label: adenylate cyclase-activating dopamine receptor signaling pathway locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: >- Principal striatal D1-like receptor; activates Golf/Gs on dopamine binding. gocam_associations: - model: gomodel:69c59f8a00000043 activity: gomodel:69c59f8a00000043/69c59f8a00000044 title: "DRD1 dopamine neurotransmitter receptor activity coupled via Gs (GO:0001588), human" description: >- Same gene and molecular function; curator-built DRD1-Gs dopamine signalling GO-CAM. - id: drd5_variant label: Dopamine receptor D5 (DRD5) module_type: REGULATORY_STEP annotons: - id: drd5_receptor label: DRD5 dopamine receptor coupled via Gs participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DRD5 term: id: UniProtKB:P21918 label: Dopamine receptor D5 function: preferred_term: dopamine neurotransmitter receptor activity, coupled via Gs term: id: GO:0001588 label: dopamine neurotransmitter receptor activity, coupled via Gs processes: - preferred_term: adenylate cyclase-activating dopamine receptor signaling pathway term: id: GO:0007191 label: adenylate cyclase-activating dopamine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Second, higher-affinity D1-like receptor; same Gs/Golf stimulatory coupling. gocam_associations: - model: gomodel:69c59f8a00003487 activity: gomodel:69c59f8a00003487/69c59f8a00003488 title: "DRD5 dopamine neurotransmitter receptor activity coupled via Gs (GO:0001588), human" - order: 2 role: adenylyl cyclase 5 synthesises cAMP node: id: dopa_adcy5 label: Adenylyl cyclase type 5 produces cAMP module_type: REACTION description: >- ADCY5 is the dominant striatal adenylyl cyclase; stimulatory G alpha-GTP activates it and inhibitory G alpha-GTP suppresses it, so it integrates the D1 and D2 inputs into the cAMP level. annotons: - id: adcy5_activity label: ADCY5 adenylate cyclase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADCY5 (adenylyl cyclase 5) term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: adenylate cyclase-activating dopamine receptor signaling pathway term: id: GO:0007191 label: adenylate cyclase-activating dopamine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Converts ATP to cAMP; the enzymatic node where the two receptor classes converge with opposite sign. evidence: - source_id: PMID:12665504 statement: >- Type 5 adenylyl cyclase accounts for the major striatal cyclase activity and for both the D1 stimulatory and D2 inhibitory responses. supporting_text: >- D1 dopaminergic agonist-stimulated adenylyl cyclase activity was attenuated, and this was accompanied by a decrease in the expression of the D1 dopaminergic receptor and G(s)alpha. D2 dopaminergic agonist-mediated inhibition of adenylyl cyclase activity was also blunted. - order: 3 role: PKA activation by cAMP node: id: dopa_pka label: cAMP-dependent protein kinase (PKA) activation module_type: REACTION description: >- cAMP binds the PKA regulatory subunits and releases the catalytic subunits (PRKACA, PRKACB, PRKACG), which phosphorylate downstream substrates including DARPP-32 at Thr34. annotons: - id: pka_catalytic label: PKA catalytic subunit activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: PKA catalytic subunits (PRKACA/PRKACB/PRKACG) term: id: GO:0005952 label: cAMP-dependent protein kinase complex description: >- The cAMP-dependent protein kinase; the catalytic subunits are the role-bearing units modelled here. active_units: - id: prkaca_unit label: PKA catalytic subunit alpha role: cAMP-dependent protein kinase catalytic activity 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 - id: prkacb_unit label: PKA catalytic subunit beta role: cAMP-dependent protein kinase catalytic activity 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 - id: prkacg_unit label: PKA catalytic subunit gamma role: cAMP-dependent protein kinase catalytic activity 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 function: preferred_term: cAMP-dependent protein kinase activity term: id: GO:0004691 label: cAMP-dependent protein kinase activity targets: - preferred_term: DARPP-32 (PPP1R1B) term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Effector kinase of the D1 arm; phosphorylates DARPP-32 at Thr34 and other substrates. The three catalytic genes are redundant paralogs. - order: 4 role: DARPP-32 phospho-Thr34 inhibition of PP1 (core integrator) node: id: dopa_darpp32_pp1 label: DARPP-32 (phospho-Thr34) inhibition of protein phosphatase 1 module_type: REGULATORY_STEP description: >- PKA phosphorylation of DARPP-32 at Thr34 converts it into a potent inhibitor of PP1, so a D1/cAMP signal both raises PKA activity and suppresses PP1-mediated dephosphorylation of PKA substrates, amplifying the response. annotons: - id: darpp32_pp1_inhibition label: DARPP-32 protein phosphatase inhibitor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP1R1B (DARPP-32) term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B function: preferred_term: protein phosphatase inhibitor activity term: id: GO:0004864 label: protein phosphatase inhibitor activity targets: - preferred_term: PP1 catalytic subunit alpha (PPP1CA) term: id: UniProtKB:P62136 label: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit processes: - preferred_term: adenylate cyclase-activating dopamine receptor signaling pathway term: id: GO:0007191 label: adenylate cyclase-activating dopamine receptor signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- The module's integrator: active only as phospho-Thr34; inhibits PP1 at nanomolar concentrations. Phospho-Thr75-DARPP-32 instead inhibits PKA (see the CDK5 regulatory step). evidence: - source_id: PMID:6087160 statement: DARPP-32 inhibits PP1 and only in its phosphorylated form. supporting_text: >- We report here that DARPP-32 inhibits protein phosphatase-1 at nanomolar concentrations. Moreover, like inhibitor-1, DARPP-32 is effective as an inhibitor in its phosphorylated but not its dephosphorylated form. - source_id: PMID:10604473 statement: >- PKA phosphorylation of Thr34 makes DARPP-32 a PP1 inhibitor; Cdk5 phosphorylation of Thr75 makes it a PKA inhibitor instead. supporting_text: >- is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34. We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). - id: pp1_catalytic label: Protein phosphatase 1 catalytic activity (target of DARPP-32) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: PP1 catalytic subunits (PPP1CA/PPP1CB/PPP1CC) term: id: GO:0000164 label: protein phosphatase type 1 complex active_units: - id: ppp1ca_unit label: PP1 catalytic subunit alpha role: protein serine/threonine phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP1CA term: id: UniProtKB:P62136 label: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity - id: ppp1cb_unit label: PP1 catalytic subunit beta role: protein serine/threonine phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP1CB term: id: UniProtKB:P62140 label: Serine/threonine-protein phosphatase PP1-beta catalytic subunit function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity - id: ppp1cc_unit label: PP1 catalytic subunit gamma role: protein serine/threonine phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP1CC term: id: UniProtKB:P36873 label: Serine/threonine-protein phosphatase PP1-gamma catalytic subunit function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- The phosphatase DARPP-32 inhibits; dephosphorylates the serine/threonine phosphoproteins that D1/PKA signalling acts on. - order: 5 role: D2-like receptor coupling to Gi/o and inhibition of adenylyl cyclase node: id: dopa_d2_gio label: D2-like dopamine receptors activate Gi/o and inhibit adenylyl cyclase module_type: REGULATORY_STEP description: >- Dopamine-occupied D2-like receptors (DRD2, DRD3, DRD4) activate the inhibitory G alpha subunits GNAI2 and GNAO1, whose GTP-bound forms inhibit ADCY5 and lower cAMP, opposing the D1 arm. concepts: - preferred_term: adenylate cyclase-inhibiting dopamine receptor signaling pathway term: id: GO:0007195 label: adenylate cyclase-inhibiting dopamine receptor signaling pathway annotons: - id: gnai2_gio label: G alpha i2 (GNAI2) G protein activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAI2 (G alpha i2) term: id: UniProtKB:P04899 label: Guanine nucleotide-binding protein G(i) subunit alpha-2 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity targets: - preferred_term: ADCY5 (adenylyl cyclase 5) term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 processes: - preferred_term: adenylate cyclase-inhibiting dopamine receptor signaling pathway term: id: GO:0007195 label: adenylate cyclase-inhibiting dopamine receptor signaling pathway locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: One of the two striatal inhibitory G alpha subunits downstream of D2-like receptors. - id: gnao1_gio label: G alpha o (GNAO1) G protein activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAO1 (G alpha o) term: id: UniProtKB:P09471 label: Guanine nucleotide-binding protein G(o) subunit alpha function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity targets: - preferred_term: ADCY5 (adenylyl cyclase 5) term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 processes: - preferred_term: adenylate cyclase-inhibiting dopamine receptor signaling pathway term: id: GO:0007195 label: adenylate cyclase-inhibiting dopamine receptor signaling pathway locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- The most abundant neuronal G alpha; the major transducer for central D2-like receptor inhibition of adenylyl cyclase. gocam_associations: - model: gomodel:69c59f8a00001396 activity: gomodel:69c59f8a00001396/69c59f8a00001398 title: "GNAO1 G protein activity (GO:0003925) in adenylate cyclase-inhibiting dopamine receptor signaling, human" description: Same gene and molecular function; curator-built DRD2-Go dopamine signalling GO-CAM. variant_sets: - id: d2_like_receptors label: D2-like dopamine receptors axis: receptor paralog selection: ONE_OR_MORE notes: >- DRD2, DRD3 and DRD4 all couple to Gi/Go and inhibit adenylyl cyclase; any (or several) satisfies this step, with DRD2 the dominant striatal D2-like receptor. variants: - id: drd2_variant label: Dopamine receptor D2 (DRD2) module_type: REGULATORY_STEP annotons: - id: drd2_receptor label: DRD2 dopamine receptor coupled via Gi/Go participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DRD2 term: id: UniProtKB:P14416 label: Dopamine receptor D2 function: preferred_term: dopamine neurotransmitter receptor activity, coupled via Gi/Go term: id: GO:0001591 label: dopamine neurotransmitter receptor activity, coupled via Gi/Go processes: - preferred_term: adenylate cyclase-inhibiting dopamine receptor signaling pathway term: id: GO:0007195 label: adenylate cyclase-inhibiting dopamine receptor signaling pathway locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: Principal striatal D2-like receptor; inhibits adenylyl cyclase via Gi/Go. gocam_associations: - model: gomodel:69c59f8a00001396 activity: gomodel:69c59f8a00001396/69c59f8a00001413 title: "DRD2 dopamine neurotransmitter receptor activity coupled via Gi/Go (GO:0001591), human" - id: drd3_variant label: Dopamine receptor D3 (DRD3) module_type: REGULATORY_STEP annotons: - id: drd3_receptor label: DRD3 dopamine receptor coupled via Gi/Go participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DRD3 term: id: UniProtKB:P35462 label: Dopamine receptor D3 function: preferred_term: dopamine neurotransmitter receptor activity, coupled via Gi/Go term: id: GO:0001591 label: dopamine neurotransmitter receptor activity, coupled via Gi/Go processes: - preferred_term: adenylate cyclase-inhibiting dopamine receptor signaling pathway term: id: GO:0007195 label: adenylate cyclase-inhibiting dopamine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: D2-like receptor enriched in limbic striatum; same Gi/Go coupling. gocam_associations: - model: gomodel:69c59f8a00002981 activity: gomodel:69c59f8a00002981/69c59f8a00002982 title: "DRD3 dopamine neurotransmitter receptor activity coupled via Gi/Go (GO:0001591), human" - id: drd4_variant label: Dopamine receptor D4 (DRD4) module_type: REGULATORY_STEP annotons: - id: drd4_receptor label: DRD4 dopamine receptor coupled via Gi/Go participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DRD4 term: id: UniProtKB:P21917 label: Dopamine receptor D4 function: preferred_term: dopamine neurotransmitter receptor activity, coupled via Gi/Go term: id: GO:0001591 label: dopamine neurotransmitter receptor activity, coupled via Gi/Go processes: - preferred_term: adenylate cyclase-inhibiting dopamine receptor signaling pathway term: id: GO:0007195 label: adenylate cyclase-inhibiting dopamine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: D2-like receptor prominent in prefrontal cortex; same Gi/Go coupling. gocam_associations: - model: gomodel:69c59f8a00003111 activity: gomodel:69c59f8a00003111/69c59f8a00003112 title: "DRD4 dopamine neurotransmitter receptor activity coupled via Gi/Go (GO:0001591), human" - order: 6 role: DARPP-32 phospho-switch kinases and phosphatases node: id: dopa_darpp32_switch label: Multisite control of the DARPP-32 phospho-switch module_type: REGULATORY_STEP description: >- DARPP-32 is a bistable switch set by phosphorylation at several residues: CDK5 at Thr75 (makes it a PKA inhibitor), two PP2A holoenzymes at Thr75 (cAMP- and Ca2+-driven), calcineurin at Thr34 (turns off PP1 inhibition), and CK1 at Ser137 (protects phospho-Thr34). These act on the DARPP-32/PP1 core of part 4. annotons: - id: cdk5_thr75 label: CDK5 phosphorylation of DARPP-32 Thr75 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CDK5 term: id: UniProtKB:Q00535 label: Cyclin-dependent kinase 5 function: preferred_term: cyclin-dependent protein serine/threonine kinase activity term: id: GO:0004693 label: cyclin-dependent protein serine/threonine kinase activity targets: - preferred_term: DARPP-32 (PPP1R1B) Thr75 term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Phosphorylates DARPP-32 at Thr75, converting it into a competitive inhibitor of PKA and so damping the D1/cAMP arm. evidence: - source_id: PMID:10604473 statement: Cdk5 phosphorylates DARPP-32 at Thr75, making it a PKA inhibitor. supporting_text: >- We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). - id: pp2a_b56delta_thr75 label: PP2A-B56delta dephosphorylation of DARPP-32 Thr75 (cAMP-driven) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: PP2A holoenzyme with B56-delta (PPP2R5D) term: id: GO:0000159 label: protein phosphatase type 2A complex description: >- The A/C core with the B56-delta regulatory subunit, the PKA-activated DARPP-32 Thr75 phosphatase. active_units: - id: pp2a_c_b56d_unit label: PP2A catalytic subunit (alpha/beta) role: protein serine/threonine phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP2CA term: id: UniProtKB:P67775 label: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity - id: pp2a_b56d_unit label: PP2A regulatory subunit B56-delta (PPP2R5D) role: >- Regulatory subunit that directs the holoenzyme to DARPP-32 Thr75 and is itself phosphorylated by PKA to raise activity. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP2R5D (B56-delta) term: id: UniProtKB:Q14738 label: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform function: preferred_term: protein phosphatase regulator activity term: id: GO:0019888 label: protein phosphatase regulator activity function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity substrates: - preferred_term: DARPP-32 (PPP1R1B) phospho-Thr75 term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- cAMP/PKA activates this holoenzyme (via PKA phosphorylation of B56-delta) to dephosphorylate Thr75, relieving the CDK5-imposed brake on PKA. evidence: - source_id: PMID:17301223 statement: >- PP2A with the B56-delta subunit is an active DARPP-32 Thr75 phosphatase, activated by PKA phosphorylation of B56-delta. supporting_text: >- We have found that the A/C subunits of PP2A, in association with the B56delta (or PPP2R5D) regulatory subunit, is an active DARPP-32 phosphatase. - source_id: PMID:17301223 statement: PKA phosphorylation of B56-delta raises PP2A activity. supporting_text: >- The B56delta subunit is phosphorylated by PKA, and this increases the overall activity of PP2A in vitro and in vivo. - id: pp2a_pr72_thr75 label: PP2A-PR72 dephosphorylation of DARPP-32 Thr75 (Ca2+-driven) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: PP2A holoenzyme with PR72 (PPP2R3A) term: id: GO:0000159 label: protein phosphatase type 2A complex description: >- The A/C core with the Ca2+-binding PR72 regulatory subunit, the Ca2+-dependent DARPP-32 Thr75 phosphatase. active_units: - id: pp2a_c_pr72_unit label: PP2A catalytic subunit (alpha/beta) role: protein serine/threonine phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP2CB term: id: UniProtKB:P62714 label: Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity - id: pp2a_pr72_unit label: PP2A regulatory subunit PR72 (PPP2R3A) role: Ca2+-binding regulatory subunit directing Ca2+-dependent Thr75 dephosphorylation. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP2R3A (PR72) term: id: UniProtKB:Q06190 label: Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha function: preferred_term: protein phosphatase regulator activity term: id: GO:0019888 label: protein phosphatase regulator activity function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity substrates: - preferred_term: DARPP-32 (PPP1R1B) phospho-Thr75 term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- The Ca2+ route to Thr75 dephosphorylation, downstream of glutamate/NMDA calcium entry; complements the cAMP route above. evidence: - source_id: PMID:17535922 statement: PP2A with the PR72 subunit mediates Ca2+-dependent Thr75 dephosphorylation. supporting_text: >- PP2A, in a heterotrimeric complex with the PR72 subunit, mediates Ca(2+)-dependent dephosphorylation at Thr-75 of DARPP-32. - id: calcineurin_thr34 label: Calcineurin dephosphorylation of DARPP-32 Thr34 participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Calcineurin catalytic subunits (PPP3CA/PPP3CB/PPP3CC) term: id: GO:0005955 label: calcineurin complex description: >- The Ca2+/calmodulin-dependent phosphatase; its catalytic A subunits are the role-bearing units. active_units: - id: ppp3ca_unit label: Calcineurin A alpha (PPP3CA) role: calmodulin-dependent protein phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP3CA term: id: UniProtKB:Q08209 label: Protein phosphatase 3 catalytic subunit alpha function: preferred_term: calmodulin-dependent protein phosphatase activity term: id: GO:0033192 label: calmodulin-dependent protein phosphatase activity - id: ppp3cb_unit label: Calcineurin A beta (PPP3CB) role: calmodulin-dependent protein phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP3CB term: id: UniProtKB:P16298 label: Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform function: preferred_term: calmodulin-dependent protein phosphatase activity term: id: GO:0033192 label: calmodulin-dependent protein phosphatase activity - id: ppp3cc_unit label: Calcineurin A gamma (PPP3CC) role: calmodulin-dependent protein phosphatase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP3CC term: id: UniProtKB:P48454 label: Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform function: preferred_term: calmodulin-dependent protein phosphatase activity term: id: GO:0033192 label: calmodulin-dependent protein phosphatase activity function: preferred_term: calmodulin-dependent protein phosphatase activity term: id: GO:0033192 label: calmodulin-dependent protein phosphatase activity substrates: - preferred_term: DARPP-32 (PPP1R1B) phospho-Thr34 term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Ca2+/calmodulin-activated; dephosphorylates Thr34, switching off DARPP-32's PP1-inhibitory activity in response to calcium. evidence: - source_id: PMID:17535922 statement: Thr34 dephosphorylation is carried out primarily by calcineurin (PP2B). supporting_text: >- Dephosphorylation at Thr-34 involves primarily the Ca(2+)-dependent protein phosphatase, PP2B (calcineurin), whereas dephosphorylation of Thr-75 involves primarily PP2A - id: csnk1a1_ser137 label: Casein kinase 1 (CSNK1A1) phosphorylation of DARPP-32 Ser137 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CSNK1A1 (casein kinase 1 alpha) term: id: UniProtKB:P48729 label: Casein kinase I isoform alpha function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity targets: - preferred_term: DARPP-32 (PPP1R1B) Ser137 term: id: UniProtKB:Q9UD71 label: Protein phosphatase 1 regulatory subunit 1B locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Phosphorylates DARPP-32 Ser137; phospho-Ser137 slows calcineurin-mediated Thr34 dephosphorylation, prolonging PP1 inhibition. The specific CK1 isoform was not resolved biochemically (see knowledge gap). evidence: - source_id: PMID:7708705 statement: CK1 phosphorylation of Ser137 inhibits calcineurin dephosphorylation of Thr34. supporting_text: >- phosphorylation of DARPP-32 on Ser-137 by casein kinase I inhibits the dephosphorylation of Thr-34 by calcineurin. - order: 7 role: receptor desensitization and G protein deactivation (termination) node: id: dopa_termination label: GRK/arrestin desensitization and RGS GTPase acceleration module_type: REGULATORY_STEP description: >- Receptor output is switched off at two levels: GRKs phosphorylate the occupied receptors so beta-arrestins uncouple and internalise them, and RGS proteins (chiefly the striatal RGS9-2/G-beta-5/R7BP complex) accelerate GTP hydrolysis on the G alpha subunits. annotons: - id: grk_receptor_phosphorylation label: GRK phosphorylation of dopamine receptors participant: selector_type: FAMILY family: preferred_term: G protein-coupled receptor kinases GRK2/GRK3/GRK5/GRK6 representative_members: - preferred_term: GRK2 term: id: UniProtKB:P25098 label: G protein-coupled receptor kinase 2 - preferred_term: GRK3 term: id: UniProtKB:P35626 label: G protein-coupled receptor kinase 3 - preferred_term: GRK5 term: id: UniProtKB:P34947 label: G protein-coupled receptor kinase 5 - preferred_term: GRK6 term: id: UniProtKB:P43250 label: G protein-coupled receptor kinase 6 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Phosphorylate agonist-occupied dopamine receptors, the first step of desensitisation; GRK6 loss causes D2-like supersensitivity. evidence: - source_id: PMID:12718862 statement: GRK6 regulates postsynaptic D2-like receptors; its loss causes supersensitivity. supporting_text: >- The present study indicates that postsynaptic D2-like dopamine receptors are physiological targets for GRK6 and suggests that this regulatory mechanism contributes to central dopaminergic supersensitivity. - id: arrestin_uncoupling label: Beta-arrestin uncoupling and internalization of dopamine receptors participant: selector_type: FAMILY family: preferred_term: beta-arrestins (ARRB1, ARRB2) representative_members: - preferred_term: ARRB1 (beta-arrestin-1) term: id: UniProtKB:P49407 label: Beta-arrestin-1 - preferred_term: ARRB2 (beta-arrestin-2) term: id: UniProtKB:P32121 label: Beta-arrestin-2 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: DRD2 term: id: UniProtKB:P14416 label: Dopamine receptor D2 processes: - preferred_term: G protein-coupled receptor internalization term: id: GO:0002031 label: G protein-coupled receptor internalization locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Bind GRK-phosphorylated receptors, block G protein coupling and drive internalisation; also seed the non-canonical signalling arm (part 9). evidence: - source_id: PMID:21303898 statement: >- Dopamine receptors are regulated by proteins implicated in desensitisation such as beta-arrestins, which also mediate G protein-independent signalling. supporting_text: >- dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. - id: rgs9_gap_complex label: RGS9-2/G-beta-5/R7BP GTPase-activating complex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: RGS9-2/G-beta-5/R7BP complex description: >- The obligate striatal R7-family GAP complex: RGS9-2 (the GAP), G-beta-5 (its obligate partner) and R7BP (the palmitoylated membrane anchor). active_units: - id: rgs9_unit label: RGS9 (RGS9-2) role: GTPase activator for the D2-coupled G alpha subunits participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS9 term: id: UniProtKB:O75916 label: Regulator of G protein signaling 9 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity - id: gnb5_unit label: G-beta-5 (GNB5) role: Obligate atypical G beta partner required for RGS9-2 stability and GAP activity. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNB5 (G-beta-5) term: id: UniProtKB:O14775 label: Guanine nucleotide-binding protein subunit beta-5 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity - id: rgs7bp_unit label: R7BP (RGS7BP) role: >- Palmitoylated membrane anchor that localises and stabilises the complex; carries no GO molecular function (scaffold), kept visible because it sets the complex's localisation. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS7BP (R7BP) term: id: UniProtKB:Q6MZT1 label: Regulator of G protein signaling 7-binding protein function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: GNAO1 (G alpha o) term: id: UniProtKB:P09471 label: Guanine nucleotide-binding protein G(o) subunit alpha processes: - preferred_term: negative regulation of G protein-coupled receptor signaling pathway term: id: GO:0045744 label: negative regulation of G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Accelerates GTP hydrolysis on the D2-coupled G alpha subunits, shortening signalling; RGS9-2 shows a strong receptor preference for D2R. evidence: - source_id: PMID:23857581 statement: RGS9-2 and RGS7 act as trimers with G-beta-5 and the R7BP anchor. supporting_text: >- Both proteins form trimeric complexes with the atypical G protein β subunit Gβ5 and a membrane anchor, R7BP. - source_id: PMID:23857581 statement: RGS9-2 GAP activity is receptor-selective for D2R. supporting_text: >- the GAP activity of RGS9-2 showed a strong receptor preference for D2R over MOR. - source_id: PMID:12818179 statement: RGS9-2 accelerates D2 receptor signalling kinetics and tunes dopamine responses in vivo. supporting_text: >- In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents variant_sets: - id: additional_rgs label: Additional striatal RGS GAPs axis: RGS paralog selection: ONE_OR_MORE notes: >- Beyond the RGS9-2 complex, the RGD text names RGS2, RGS4 and RGS7 as GAPs acting on the dopamine-pathway G alpha subunits; RGS7 also partners G-beta-5 and R7BP. variants: - id: rgs7_variant label: RGS7 module_type: REGULATORY_STEP annotons: - id: rgs7_gap label: RGS7 GTPase activator activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS7 term: id: UniProtKB:P49802 label: Regulator of G protein signaling 7 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity processes: - preferred_term: negative regulation of G protein-coupled receptor signaling pathway term: id: GO:0045744 label: negative regulation of G protein-coupled receptor signaling pathway role_description: R7-family GAP for Go; partners G-beta-5 and R7BP, remodelled with RGS9-2. evidence: - source_id: PMID:19332565 statement: R7 RGS proteins (RGS9-2, RGS7) function as complexes with G-beta-5 and R7BP. supporting_text: >- R7 RGS proteins function as macromolecular complexes with two subunits: type 5 G protein beta (Gbeta5) and R7 binding protein (R7BP). - id: rgs4_variant label: RGS4 module_type: REGULATORY_STEP annotons: - id: rgs4_gap label: RGS4 GTPase activator activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS4 term: id: UniProtKB:P49798 label: Regulator of G protein signaling 4 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity processes: - preferred_term: negative regulation of G protein-coupled receptor signaling pathway term: id: GO:0045744 label: negative regulation of G protein-coupled receptor signaling pathway role_description: Striatal GAP named by the RGD diagram's RGS node. - id: rgs2_variant label: RGS2 module_type: REGULATORY_STEP annotons: - id: rgs2_gap label: RGS2 GTPase activator activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS2 term: id: UniProtKB:P41220 label: Regulator of G protein signaling 2 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity processes: - preferred_term: negative regulation of G protein-coupled receptor signaling pathway term: id: GO:0045744 label: negative regulation of G protein-coupled receptor signaling pathway role_description: GAP named by the RGD diagram's RGS node. - order: 8 role: DARPP-32/PP1 control of STEP and the ERK branch node: id: dopa_step_erk label: STEP (PTPN5) regulation of ERK downstream of PP1 module_type: REGULATORY_STEP description: >- Dopamine signalling reaches the ERK cascade through DARPP-32/PP1. The striatal tyrosine phosphatase STEP (PTPN5) dephosphorylates and inactivates ERK; PKA keeps STEP phosphorylated and inactive, while PP1 (and Ca2+/calcineurin) dephosphorylate and activate it, so PP1 inhibition by DARPP-32 sustains ERK activity. annotons: - id: ptpn5_step label: STEP (PTPN5) tyrosine phosphatase inactivation of ERK participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTPN5 (STEP) term: id: UniProtKB:P54829 label: Tyrosine-protein phosphatase non-receptor type 5 function: preferred_term: protein tyrosine phosphatase activity term: id: GO:0004725 label: protein tyrosine phosphatase activity processes: - preferred_term: negative regulation of ERK1 and ERK2 cascade term: id: GO:0070373 label: negative regulation of ERK1 and ERK2 cascade locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Dephosphorylates the ERK activation-loop tyrosine; inactive when PKA-phosphorylated, active when PP1 dephosphorylates it, so it links the cAMP/PP1 core to ERK. evidence: - source_id: PMID:12483215 statement: Calcineurin dephosphorylation activates STEP, which limits ERK activity. supporting_text: >- activation of NMDA receptors led to activation of STEP, which limited the duration of ERK activity - source_id: PMID:15608059 statement: PKA phosphorylation inactivates STEP; PP1 (controlled by DARPP-32) dephosphorylates and activates it. supporting_text: >- Phosphatases of the STEP family lose their ability to dephosphorylate ERK when they are phosphorylated by PKA on a regulatory serine residue within their ERK-binding domain, termed the kinase interaction motif - order: 9 role: non-canonical beta-arrestin 2 / PP2A / AKT arm (D2) optional: true node: id: dopa_arrestin_akt label: ARRB2/PP2A/AKT G protein-independent arm module_type: REGULATORY_STEP description: >- D2-class receptors also signal independently of G proteins: beta-arrestin-2 scaffolds PP2A onto AKT, lowering AKT activity and thereby disinhibiting GSK3. This arm is slower and distinct from the cAMP cascade. concepts: - preferred_term: beta-arrestin-dependent dopamine receptor signaling pathway term: id: GO:0160213 label: beta-arrestin-dependent dopamine receptor signaling pathway annotons: - id: arrb2_akt_scaffold label: Beta-arrestin-2 scaffolding of PP2A onto AKT participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ARRB2 (beta-arrestin-2) term: id: UniProtKB:P32121 label: Beta-arrestin-2 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: AKT1 term: id: UniProtKB:P31749 label: RAC-alpha serine/threonine-protein kinase - preferred_term: PPP2CA (PP2A catalytic) term: id: UniProtKB:P67775 label: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform processes: - preferred_term: beta-arrestin-dependent dopamine receptor signaling pathway term: id: GO:0160213 label: beta-arrestin-dependent dopamine receptor signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Assembles an AKT/beta-arrestin-2/PP2A complex downstream of D2 receptors; this is the adaptor function, distinct from desensitisation. evidence: - source_id: PMID:16051150 statement: D2-receptor-mediated Akt regulation runs through a beta-arrestin-2/PP2A/Akt complex. supporting_text: >- D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. - source_id: PMID:16051150 statement: This arm is independent of the canonical cAMP cascade. supporting_text: >- canonical cAMP-mediated dopamine-receptor signaling is not inhibited in the absence of beta-arrestin 2. - id: akt_deactivation label: AKT deactivation (target of the arrestin/PP2A complex) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKT1 term: id: UniProtKB:P31749 label: RAC-alpha serine/threonine-protein kinase function: preferred_term: protein serine kinase activity term: id: GO:0106310 label: protein serine kinase activity targets: - preferred_term: GSK3B term: id: UniProtKB:P49841 label: Glycogen synthase kinase-3 beta processes: - preferred_term: beta-arrestin-dependent dopamine receptor signaling pathway term: id: GO:0160213 label: beta-arrestin-dependent dopamine receptor signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- PP2A dephosphorylation lowers AKT activity in this complex; because AKT phosphorylation of GSK3 is inhibitory, GSK3B is disinhibited. evidence: - source_id: PMID:16051150 statement: Dopamine regulates striatal Akt and its interaction with PP2A via beta-arrestin-2. supporting_text: >- beta-arrestin 2 deficiency in mice results in reduction of dopamine-dependent behaviors, loss of Akt regulation by dopamine in the striatum connections: - source: dopa_d1_golf target: dopa_adcy5 connection_type: POSITIVELY_REGULATES description: D1-like receptors via Golf/Gs stimulate ADCY5. - source: dopa_adcy5 target: dopa_pka connection_type: PROVIDES_INPUT_FOR description: cAMP produced by ADCY5 activates PKA. - source: dopa_pka target: dopa_darpp32_pp1 connection_type: POSITIVELY_REGULATES description: PKA phosphorylates DARPP-32 Thr34, activating its PP1-inhibitory function. - source: dopa_d2_gio target: dopa_adcy5 connection_type: NEGATIVELY_REGULATES description: D2-like receptors via Gi/o inhibit ADCY5, lowering cAMP. - source: dopa_darpp32_switch target: dopa_darpp32_pp1 connection_type: NEGATIVELY_REGULATES description: >- CDK5 (Thr75) and calcineurin (Thr34) oppose the active DARPP-32/PP1-inhibitory state, while the PP2A holoenzymes and CK1 tune the switch. - source: dopa_pka target: dopa_darpp32_switch connection_type: POSITIVELY_REGULATES description: >- PKA activates the B56-delta PP2A holoenzyme (via B56-delta phosphorylation), the cAMP route to Thr75 dephosphorylation. - source: dopa_termination target: dopa_d1_golf connection_type: NEGATIVELY_REGULATES description: GRK/arrestin desensitisation and RGS GAP activity terminate D1-like signalling. - source: dopa_termination target: dopa_d2_gio connection_type: NEGATIVELY_REGULATES description: >- GRK/arrestin desensitisation and the RGS9-2 complex (D2-selective GAP) terminate D2-like signalling. - source: dopa_darpp32_pp1 target: dopa_step_erk connection_type: POSITIVELY_REGULATES description: >- DARPP-32 inhibition of PP1 keeps STEP phosphorylated/inactive, sustaining ERK activity downstream of D1 signalling. - source: dopa_d2_gio target: dopa_arrestin_akt connection_type: PROVIDES_INPUT_FOR description: D2-class receptors seed the G protein-independent beta-arrestin-2/PP2A/AKT arm.