id: MODULE:visual_phototransduction title: Visual phototransduction — opsin, transducin, PDE6 and CNG-channel activation cascade in rods and cones, with GRK/arrestin, RGS9 and GCAP/retGC recovery; RHO/OPN1SW/OPN1MW/OPN1LW/GNAT1/GNAT2/PDE6/CNGA1/CNGA3/SLC24A1/GRK1/SAG/RGS9/GUCY2D description: >- Vertebrate visual phototransduction converts the absorption of a photon by a visual pigment in the outer segment of a rod or cone photoreceptor into a hyperpolarisation of the photoreceptor plasma membrane. The visual pigment is an opsin, a G protein-coupled receptor that carries covalently bound 11-cis-retinal: rhodopsin (RHO) in rods, and the short-, medium- and long-wavelength cone opsins (OPN1SW, OPN1MW, OPN1LW) in the three classes of human cone. Photoisomerisation of the chromophore to all-trans-retinal activates the opsin, which catalyses GDP/GTP exchange on many molecules of the photoreceptor G protein transducin (rod GNAT1 with GNB1 and GNGT1; cone GNAT2 with GNB3 and GNGT2). GTP-bound transducin alpha binds the inhibitory gamma subunits of the cGMP phosphodiesterase PDE6 (rod PDE6A/PDE6B catalytic heterodimer with PDE6G; cone PDE6C homodimer with PDE6H) and relieves their inhibition. Activated PDE6 hydrolyses cGMP. The fall in cytoplasmic cGMP closes the cGMP-gated cation (CNG) channels of the outer-segment plasma membrane (rod CNGA1/CNGB1; cone CNGA3/CNGB3) that carry the inward dark current, and the cell hyperpolarises. Because the potassium-dependent sodium/calcium exchanger of the outer segment (rod SLC24A1, cone SLC24A2) continues to extrude Ca2+ while the channels are closed, cytoplasmic Ca2+ falls. Recovery has three arms. The opsin is phosphorylated by rhodopsin kinase (GRK1 in rods; GRK1 and GRK7 in human cones) and then capped by arrestin (rod arrestin SAG, cone arrestin ARR3), which blocks further transducin activation; Ca2+-bound recoverin (RCVRN) inhibits rhodopsin kinase in darkness, so the fall in Ca2+ speeds opsin shut-off. Transducin is switched off by its own GTPase, accelerated by a GTPase-activating complex of RGS9-1, the long isoform of GNB5 and the membrane anchor RGS9BP (R9AP). cGMP is resynthesised by the membrane retinal guanylate cyclases (GUCY2D/RetGC1 and GUCY2F/RetGC2), which are stimulated by the Ca2+-free form of the guanylate cyclase-activating proteins GCAP1 (GUCA1A) and GCAP2 (GUCA1B); the light-induced fall in Ca2+ thus drives cGMP resynthesis and channel reopening. The chromophore released by bleaching is regenerated by the separate retinoid visual cycle. Loss-of-function variants across the cascade cause inherited retinal disease, including achromatopsia (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H), retinitis pigmentosa (RHO, PDE6A, PDE6B, CNGA1, CNGB1), congenital stationary night blindness (RHO, GNAT1, SAG and GRK1 in Oguchi disease, SLC24A1), bradyopsia (RGS9, RGS9BP) and GUCY2D Leber congenital amaurosis. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000962 title: visual phototransduction pathway statement: >- The module boundary and its core gene products follow the RGD interactive diagram for this Pathway Ontology term. The diagram draws light acting on 11-cis-retinal; Rho positively affecting Gnat1 and the cone opsins positively affecting Gnat2; Gnat1 and Gnat2 each positively affecting the Pde6 complex; the CNG channel subunits Cnga1, Cngb1, Cnga3 and Cngb3 and the exchangers Slc24a1 and Slc24a2; Grk1, Grk7, Sag, Arr3 and Rcvrn (with Ca-in acting on Rcvrn); Ca efflux acting on Guca1a and Guca1b, and Guca1a acting on Gucy2e and Guca1b on Gucy2f; membrane hyperpolarisation; and glutamate output to rod and ON/OFF cone bipolar cells. The record's human gene list adds the transducin beta/gamma subunits (GNB1, GNB3, GNGT1, GNGT2), the PDE6 subunits (PDE6A, PDE6B, PDE6C, PDE6G, PDE6H), the RGS9 GAP complex (RGS9, GNB5, RGS9BP), OPN1SW/OPN1MW/OPN1LW and CIMIP3. The retinoid cycle (PW:0001005) is drawn as a subpathway. Derived through projects/RGD_PATHWAY_ONTOLOGY (module seed PW:0000962). - source_id: GO:0007602 title: phototransduction statement: >- GO phototransduction is the closeMatch recorded for PW:0000962 in the project's module seeds; GO:0007603 phototransduction, visible light is its relatedMatch. The module is grounded in the more specific descendant GO:0141190 transducin-mediated opsin signaling pathway, whose definition spans the transducin, PDE6 and CNG-channel steps and the GRK/arrestin termination modelled here. - source_id: PMID:11095744 title: Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha -subunit. statement: >- Transducin couples rhodopsin to the cascade, and rods depend on a single transducin alpha subunit. supporting_text: Retinal photoreceptors use the heterotrimeric G protein transducin to couple rhodopsin to a biochemical cascade that underlies the electrical photoresponse. - source_id: PMID:7682292 title: A new subunit of the cyclic nucleotide-gated cation channel in retinal rods. statement: >- States the core logic of the cascade: G-protein-mediated cGMP hydrolysis closes the cGMP-gated channel that is open in darkness, hyperpolarising the rod. supporting_text: Retinal rods respond to light with a membrane hyperpolarization produced by a G-protein-mediated signalling cascade that leads to cyclic GMP hydrolysis and the consequent closure of a cGMP-gated channel that is open in darkness. - source_id: PMID:10662833 title: Molecular cloning and functional expression of the potassium-dependent sodium-calcium exchanger from human and chicken retinal cone photoreceptors. statement: >- The light-induced fall in outer-segment Ca2+, which drives the Ca2+-feedback arms of recovery, is caused by continued Na-Ca+K exchange. supporting_text: This light-induced lowering of calcium is caused by extrusion via a Na-Ca exchanger located in the rod and cone outer segment plasma membrane and plays a key role in the process of light adaptation. notes: >- Derived from the RGD Pathway Ontology diagram PW:0000962 through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. The RGD diagram and its human gene list supplied the boundary, the 32 retained gene products and the topology; GUCA1A was added and CIMIP3 excluded (below). Rods and cones run the same cascade with cell-type-specific paralogs, so each step is a part whose rod and cone implementations are variants on the axis "photoreceptor cell type" (selection ONE_OR_MORE, because a retina has both); steps whose proteins serve both cell types (recoverin, the RGS9 GAP complex, the retGC/GCAP pair) are plain annotons. Within the cone photon-capture variant, the three cone opsins are a nested ONE_OR_MORE variant set on spectral class. Rhodopsin kinase is a variant set on kinase (GRK1, GRK7) rather than on cell type because human cones express both, while rods express only GRK1 (PMID:15946941). Molecular functions were taken from each protein's GO annotations in QuickGO and the cached literature: opsins G protein-coupled photoreceptor activity GO:0008020 (OPN1LW IDA PMID:21314100; OPN1MW IDA); transducin alpha G protein activity GO:0003925 (GNAT2 IMP PMID:12077706); PDE6 catalytic subunits 3',5'-cyclic-GMP phosphodiesterase activity GO:0047555 (PDE6A/B IDA PMID:20940301; PDE6C IDA PMID:21127010) and PDE6 gamma subunits enzyme inhibitor activity GO:0004857, matching the GO-CAMs; CNG subunits intracellularly cGMP-activated cation channel activity GO:0005223 (IDA, and the completed CNGA1/CNGB1/CNGA3/CNGB3 reviews); NCKX calcium, potassium:sodium antiporter activity GO:0008273 (IDA PMID:10662833); GRK1/GRK7 rhodopsin kinase activity GO:0050254 (IDA PMID:15946941); RGS9 GTPase activator activity GO:0005096 (IMP PMID:14702087); GCAPs calcium sensitive guanylate cyclase activator activity GO:0008048; retGCs guanylate cyclase activity GO:0004383 (GUCY2D IDA). Two functions are asserted here although GOA lacks them. Arrestin is given signaling receptor inhibitor activity GO:0030547 because its GOA molecular functions are opsin binding (IEA/ISS), G protein-coupled receptor binding (IBA) and protein sequestering activity (IDA, PMID:26200343), none of which states that arrestin binding stops the receptor activating transducin, which is the role in this pathway (PMID:9333241, PMID:26200343). Recoverin is given protein kinase inhibitor activity GO:0004860, with rhodopsin kinase as target, from the Ca2+-dependent inhibition of rhodopsin phosphorylation by recoverin/S-modulin (PMID:8386803). RCVRN's only non-binding GOA molecular function, calcium sensitive guanylate cyclase activator activity GO:0008048, is a TAS row citing PMID:1672047. That paper is the 1991 report that named recoverin as a guanylate cyclase activator, a role later assigned to the GCAPs (PMID:9702199, PMID:11493703), so the GOA row is not used here; PMID:1672047 is not cached and its full text was not read, so this is flagged rather than asserted as an error. GUCA1A (GCAP1) is added although it is absent from RGD's human gene list: the RGD diagram itself draws Guca1a acting on Gucy2e, and GCAP1 is the principal Ca2+-sensitive activator of retGC in rods and cones (PMID:9702199; the GCAPs knockout removes both GCAP1 and GCAP2, PMID:11493703). Its absence from the human list most likely comes from the gene-mapping route rather than biology, because the list instead contains CIMIP3, whose HGNC alias is GUCA1ANB ("GUCA1A neighbor"). CIMIP3 (UniProtKB:X6R8D5) is a ciliary microtubule inner protein of the sperm flagellar axoneme with no known role in phototransduction, so it is excluded. The RGD diagram node Gucy2e is the rodent gene for RetGC1; its human ortholog is GUCY2D, as on the human gene list. The human OPN1MW tandem array also yields OPN1MW2 and OPN1MW3, which have their own GO-CAMs; only OPN1MW, as listed by RGD, is grounded here. Out of scope: the retinoid visual cycle that regenerates 11-cis-retinal, which is referenced as a part through module_ref retinoid_visual_cycle and not duplicated; synaptic glutamate release and bipolar-cell signalling, which the diagram draws as outputs; opsin biosynthesis and outer-segment transport and morphogenesis; the soluble GARP splice products of CNGB1 that inhibit basal PDE6 (see the CNGB1 gene review); and GUCA1C (GCAP3), which is not on the RGD list. Six human GO-CAMs, one per visual pigment (RHO, OPN1SW, OPN1MW, OPN1MW2, OPN1MW3 and OPN1LW models; gomodel:6918f23700000035, 69ea894900003713, 69ea894900003563, 69ea894900003638, 68fac5ed00003700, 68fac5ed00003872), model the activation chain opsin -> transducin alpha -> PDE6 gamma -> PDE6 catalytic -> CNG channel; their activities are linked on the matching annotons below. None of them models the recovery steps, NCKX or GUCY2D/GCAP. In the OPN1SW, OPN1MW, OPN1MW2 and OPN1MW3 models the PDE6C activity is part_of GO:0070966 nuclear-transcribed mRNA catabolic process, no-go decay, whereas the OPN1LW model places the same activity in GO:0141190; the no-go decay term appears to be a curation slip and is worth reporting to the model's curator. There are completed gene reviews only for the four CNG subunits; all other molecular functions were taken from QuickGO and the literature directly. module: id: visual_phototransduction label: Visual phototransduction module_type: SIGNALING_PATHWAY concepts: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway description: >- Photon-activated opsin activates transducin, transducin alpha activates PDE6, the fall in cGMP closes CNG channels and hyperpolarises the photoreceptor, and the signal is terminated by opsin phosphorylation and arrestin binding. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the rod and cone cascades are conserved across vertebrates. cell_types: - preferred_term: retinal rod cell term: id: CL:0000604 label: retinal rod cell - preferred_term: retinal cone cell term: id: CL:0000573 label: retinal cone cell cellular_components: - preferred_term: photoreceptor outer segment term: id: GO:0001750 label: photoreceptor outer segment description: >- All steps run in the outer segment; disc-membrane and plasma-membrane locations are given on the individual annotons. parts: - order: 1 role: photon capture by the visual pigment node: id: phototransduction_photon_capture label: Opsin photoactivation module_type: REGULATORY_STEP description: >- Absorption of a photon isomerises the 11-cis-retinal chromophore, converting the opsin into its active state, which binds and activates transducin. variant_sets: - id: photon_capture_cell_type label: Rod and cone visual pigments axis: photoreceptor cell type selection: ONE_OR_MORE variants: - id: rod_photon_capture label: Rhodopsin (rods) module_type: REGULATORY_STEP annotons: - id: rho_photoreceptor_activity label: Rhodopsin (RHO) G protein-coupled photoreceptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RHO (rhodopsin) term: id: UniProtKB:P08100 label: Rhodopsin function: preferred_term: G protein-coupled photoreceptor activity term: id: GO:0008020 label: G protein-coupled photoreceptor activity targets: - preferred_term: GNAT1 (rod transducin alpha) term: id: UniProtKB:P11488 label: Guanine nucleotide-binding protein G(t) subunit alpha-1 processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: rod photoreceptor disc membrane term: id: GO:0120202 label: rod photoreceptor disc membrane role_description: >- Dim-light visual pigment of rods; photoactivated rhodopsin catalyses nucleotide exchange on rod transducin. evidence: - source_id: PMID:11095744 statement: Transducin couples rhodopsin to the rod cascade. supporting_text: Retinal photoreceptors use the heterotrimeric G protein transducin to couple rhodopsin to a biochemical cascade that underlies the electrical photoresponse. gocam_associations: - model: gomodel:6918f23700000035 activity: gomodel:6918f23700000035/6918f23700000045 title: RHO G protein-coupled photoreceptor activity (GO:0008020) in the rod photoreceptor disc membrane description: >- Same gene and molecular function; directly positively regulates the GNAT1 activity in that model. - id: cone_photon_capture label: Cone opsins (cones) module_type: REGULATORY_STEP variant_sets: - id: cone_opsin_spectral_class label: Cone opsin spectral classes axis: spectral class selection: ONE_OR_MORE notes: >- Each cone expresses one opsin; trichromatic vision needs all three classes, but each class runs the same cone cascade. variants: - id: s_cone_opsin label: Short-wavelength cone opsin (OPN1SW) module_type: REGULATORY_STEP annotons: - id: opn1sw_photoreceptor_activity label: OPN1SW G protein-coupled photoreceptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: OPN1SW (blue cone opsin) term: id: UniProtKB:P03999 label: Short-wave-sensitive opsin 1 function: preferred_term: G protein-coupled photoreceptor activity term: id: GO:0008020 label: G protein-coupled photoreceptor activity targets: - preferred_term: GNAT2 (cone transducin alpha) term: id: UniProtKB:P19087 label: Guanine nucleotide-binding protein G(t) subunit alpha-2 processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: cone photoreceptor disc membrane term: id: GO:0120201 label: cone photoreceptor disc membrane role_description: Visual pigment of short-wavelength (blue) cones. gocam_associations: - model: gomodel:69ea894900003713 activity: gomodel:69ea894900003713/69ea894900003714 title: OPN1SW G protein-coupled photoreceptor activity (GO:0008020) in the cone photoreceptor disc membrane description: Same gene and molecular function; upstream of GNAT2 in that model. - id: m_cone_opsin label: Medium-wavelength cone opsin (OPN1MW) module_type: REGULATORY_STEP annotons: - id: opn1mw_photoreceptor_activity label: OPN1MW G protein-coupled photoreceptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: OPN1MW (green cone opsin) term: id: UniProtKB:P04001 label: Medium-wave-sensitive opsin 1 function: preferred_term: G protein-coupled photoreceptor activity term: id: GO:0008020 label: G protein-coupled photoreceptor activity targets: - preferred_term: GNAT2 (cone transducin alpha) term: id: UniProtKB:P19087 label: Guanine nucleotide-binding protein G(t) subunit alpha-2 processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: cone photoreceptor disc membrane term: id: GO:0120201 label: cone photoreceptor disc membrane role_description: >- Visual pigment of medium-wavelength (green) cones; the OPN1MW2/OPN1MW3 copies of the tandem array encode the same role. gocam_associations: - model: gomodel:69ea894900003563 activity: gomodel:69ea894900003563/69ea894900003564 title: OPN1MW G protein-coupled photoreceptor activity (GO:0008020) in the cone photoreceptor disc membrane description: Same gene and molecular function; upstream of GNAT2 in that model. - id: l_cone_opsin label: Long-wavelength cone opsin (OPN1LW) module_type: REGULATORY_STEP annotons: - id: opn1lw_photoreceptor_activity label: OPN1LW G protein-coupled photoreceptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: OPN1LW (red cone opsin) term: id: UniProtKB:P04000 label: Long-wave-sensitive opsin 1 function: preferred_term: G protein-coupled photoreceptor activity term: id: GO:0008020 label: G protein-coupled photoreceptor activity targets: - preferred_term: GNAT2 (cone transducin alpha) term: id: UniProtKB:P19087 label: Guanine nucleotide-binding protein G(t) subunit alpha-2 processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: cone photoreceptor disc membrane term: id: GO:0120201 label: cone photoreceptor disc membrane role_description: Visual pigment of long-wavelength (red) cones. evidence: - source_id: PMID:21314100 statement: >- Human red cone opsin activates transducin in a ligand-dependent manner. supporting_text: the effects of full-length and truncated retinal analogues on the human red cone opsin's ability to activate transducin, the G protein in visual transduction, were assessed. gocam_associations: - model: gomodel:68fac5ed00003872 activity: gomodel:68fac5ed00003872/68fac5ed00003882 title: OPN1LW G protein-coupled photoreceptor activity (GO:0008020) in the cone photoreceptor disc membrane description: >- Same gene and molecular function; directly positively regulates GNAT2 in that model. - order: 2 role: transducin activation node: id: phototransduction_transducin label: Transducin activation module_type: REGULATORY_STEP description: >- The photoactivated opsin catalyses GDP/GTP exchange on the transducin alpha subunit; GTP-bound alpha separates from the beta-gamma dimer and engages PDE6. variant_sets: - id: transducin_cell_type label: Rod and cone transducins axis: photoreceptor cell type selection: ONE_OR_MORE variants: - id: rod_transducin label: Rod transducin (GNAT1/GNB1/GNGT1) module_type: REGULATORY_STEP annotons: - id: rod_transducin_activity label: Rod transducin G protein activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: rod transducin heterotrimer term: id: GO:0005834 label: heterotrimeric G-protein complex active_units: - id: gnat1_unit label: GNAT1 alpha subunit role: Binds GDP/GTP; GTP-bound GNAT1 activates PDE6. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAT1 term: id: UniProtKB:P11488 label: Guanine nucleotide-binding protein G(t) subunit alpha-1 - id: gnb1_unit label: GNB1 beta subunit role: Beta-gamma dimer required for receptor coupling of the alpha subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNB1 term: id: UniProtKB:P62873 label: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 - id: gngt1_unit label: GNGT1 gamma subunit role: Farnesylated gamma subunit anchoring the beta-gamma dimer to the disc membrane. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNGT1 term: id: UniProtKB:P63211 label: Guanine nucleotide-binding protein G(T) subunit gamma-T1 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity targets: - preferred_term: PDE6G (rod PDE6 gamma) term: id: UniProtKB:P18545 label: Rod cGMP 3',5'-cyclic phosphodiesterase subunit gamma processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: rod photoreceptor disc membrane term: id: GO:0120202 label: rod photoreceptor disc membrane role_description: >- Rod G protein; rods depend on GNAT1 for phototransduction. evidence: - source_id: PMID:11095744 statement: >- Deleting the rod transducin alpha subunit abolishes rod responses; rods use a single transducin. supporting_text: These results indicate that most if not all rods use a single transducin type in phototransduction. gocam_associations: - model: gomodel:6918f23700000035 activity: gomodel:6918f23700000035/6918f23700000053 title: GNAT1 G protein activity (GO:0003925) in the rod photoreceptor disc membrane description: >- Same molecular function, enabled by the GNAT1 alpha subunit alone in that model; directly negatively regulates the PDE6G inhibitor. - id: cone_transducin label: Cone transducin (GNAT2/GNB3/GNGT2) module_type: REGULATORY_STEP annotons: - id: cone_transducin_activity label: Cone transducin G protein activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: cone transducin heterotrimer term: id: GO:0005834 label: heterotrimeric G-protein complex active_units: - id: gnat2_unit label: GNAT2 alpha subunit role: Binds GDP/GTP; GTP-bound GNAT2 activates cone PDE6. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAT2 term: id: UniProtKB:P19087 label: Guanine nucleotide-binding protein G(t) subunit alpha-2 - id: gnb3_unit label: GNB3 beta subunit role: Cone beta subunit of the beta-gamma dimer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNB3 term: id: UniProtKB:P16520 label: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 - id: gngt2_unit label: GNGT2 gamma subunit role: Cone gamma subunit of the beta-gamma dimer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNGT2 term: id: UniProtKB:O14610 label: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity targets: - preferred_term: PDE6H (cone PDE6 gamma) term: id: UniProtKB:Q13956 label: Retinal cone rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: cone photoreceptor disc membrane term: id: GO:0120201 label: cone photoreceptor disc membrane role_description: Cone G protein; loss of GNAT2 causes achromatopsia. evidence: - source_id: PMID:12077706 statement: GNAT2 is the cone transducin alpha subunit, and its loss causes achromatopsia. supporting_text: GNAT2 encodes the cone photoreceptor-specific alpha-subunit of transducin, a G-protein of the phototransduction cascade, which couples to the visual pigment(s). gocam_associations: - model: gomodel:68fac5ed00003872 activity: gomodel:68fac5ed00003872/68fac5ed00003890 title: GNAT2 G protein activity (GO:0003925), OPN1LW model description: >- Same molecular function enabled by GNAT2; directly negatively regulates the PDE6H inhibitor in that model. - model: gomodel:69ea894900003713 activity: gomodel:69ea894900003713/69ea894900003722 title: GNAT2 G protein activity (GO:0003925), OPN1SW model - model: gomodel:69ea894900003563 activity: gomodel:69ea894900003563/69ea894900003572 title: GNAT2 G protein activity (GO:0003925), OPN1MW model - order: 3 role: PDE6 activation and cGMP hydrolysis node: id: phototransduction_pde6 label: PDE6 activation and cGMP hydrolysis module_type: REACTION description: >- PDE6 is held inactive in darkness by its gamma subunits. GTP-bound transducin alpha binds the gamma subunits and relieves inhibition of the catalytic subunits, which hydrolyse cGMP to 5'-GMP. variant_sets: - id: pde6_cell_type label: Rod and cone PDE6 axis: photoreceptor cell type selection: ONE_OR_MORE variants: - id: rod_pde6 label: Rod PDE6 (PDE6A/PDE6B/PDE6G) module_type: REACTION annotons: - id: rod_pde6_catalysis label: Rod PDE6AB 3',5'-cyclic-GMP phosphodiesterase activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: rod PDE6 (PDE6A/PDE6B catalytic core of the GO:7770030 holoenzyme) term: id: GO:7770030 label: rod photoreceptor phosphodiesterase 6 complex active_units: - id: pde6a_unit label: PDE6A catalytic subunit role: Catalytic subunit, enzymatically equivalent to PDE6B. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE6A term: id: UniProtKB:P16499 label: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha - id: pde6b_unit label: PDE6B catalytic subunit role: Catalytic subunit, enzymatically equivalent to PDE6A. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE6B term: id: UniProtKB:P35913 label: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta function: preferred_term: 3',5'-cyclic-GMP phosphodiesterase activity term: id: GO:0047555 label: 3',5'-cyclic-GMP phosphodiesterase activity substrates: - preferred_term: 3',5'-cyclic GMP products: - preferred_term: 5'-GMP processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: rod photoreceptor disc membrane term: id: GO:0120202 label: rod photoreceptor disc membrane role_description: >- Effector enzyme of the rod cascade. GO:7770030 is the holoenzyme (PDE6A/PDE6B with two PDE6G); only the catalytic subunits are active units here, and PDE6G is a separate annoton whose inhibition targets the same complex, as in GO-CAM 6918f23700000035. evidence: - source_id: PMID:20940301 statement: Rod PDE6 catalytic core is the PDE6A/PDE6B heterodimer. supporting_text: The catalytic core of rod PDE6 is a unique heterodimer of PDE6A and PDE6B catalytic subunits. gocam_associations: - model: gomodel:6918f23700000035 activity: gomodel:6918f23700000035/6918f23700001883 title: PDE6A/PDE6B complex 3',5'-cyclic-GMP phosphodiesterase activity (GO:0047555) description: >- Same complex and molecular function; directly negatively regulates the CNGA1/CNGB1 channel in that model. - id: pde6g_inhibition label: PDE6G inhibitory gamma subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE6G term: id: UniProtKB:P18545 label: Rod cGMP 3',5'-cyclic phosphodiesterase subunit gamma function: preferred_term: enzyme inhibitor activity term: id: GO:0004857 label: enzyme inhibitor activity targets: - preferred_term: PDE6A/PDE6B term: id: GO:7770030 label: rod photoreceptor phosphodiesterase 6 complex processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: rod photoreceptor disc membrane term: id: GO:0120202 label: rod photoreceptor disc membrane role_description: >- Keeps rod PDE6 inactive in darkness; bound and displaced by GTP-bound GNAT1 on activation. evidence: - source_id: PMID:20940301 statement: Rod and cone gamma subunits inhibit PDE6 with comparable potency. supporting_text: Likewise, the K(i) values for PDE6C, PDE6C-A, and PDE6C-B inhibition by the cone- and rod-specific PDE6 γ-subunits (Pγ) were comparable. gocam_associations: - model: gomodel:6918f23700000035 activity: gomodel:6918f23700000035/6918f23700000036 title: PDE6G enzyme inhibitor activity (GO:0004857) description: Same gene and molecular function; inhibits the PDE6A/PDE6B activity in that model. - id: cone_pde6 label: Cone PDE6 (PDE6C/PDE6H) module_type: REACTION annotons: - id: cone_pde6_catalysis label: Cone PDE6C 3',5'-cyclic-GMP phosphodiesterase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE6C (homodimeric catalytic core) term: id: UniProtKB:P51160 label: Cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha' function: preferred_term: 3',5'-cyclic-GMP phosphodiesterase activity term: id: GO:0047555 label: 3',5'-cyclic-GMP phosphodiesterase activity substrates: - preferred_term: 3',5'-cyclic GMP products: - preferred_term: 5'-GMP processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: cone photoreceptor disc membrane term: id: GO:0120201 label: cone photoreceptor disc membrane role_description: Effector enzyme of the cone cascade; loss causes achromatopsia. evidence: - source_id: PMID:21127010 statement: PDE6C is the cone PDE6 catalytic subunit, mutated in achromatopsia. supporting_text: Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia - source_id: PMID:20940301 statement: Cone and rod transducin alpha both activate cone PDE6C. supporting_text: Recombinant cone transducin-α (Gα(t2)) and native rod Gα(t1) fully and potently activated PDE6C, PDE6C-A, and PDE6C-B. gocam_associations: - model: gomodel:68fac5ed00003872 activity: gomodel:68fac5ed00003872/69ea894900000234 title: PDE6C 3',5'-cyclic-GMP phosphodiesterase activity (GO:0047555), OPN1LW model description: >- Same gene and molecular function, part_of GO:0141190 in that model. - model: gomodel:69ea894900003713 activity: gomodel:69ea894900003713/69ea894900003751 title: PDE6C 3',5'-cyclic-GMP phosphodiesterase activity (GO:0047555), OPN1SW model description: >- Same gene and molecular function; the model places it part_of GO:0070966 no-go decay, apparently in error (see module notes). - model: gomodel:69ea894900003563 activity: gomodel:69ea894900003563/69ea894900003601 title: PDE6C 3',5'-cyclic-GMP phosphodiesterase activity (GO:0047555), OPN1MW model description: >- Same gene and molecular function; the model places it part_of GO:0070966 no-go decay, apparently in error (see module notes). - id: pde6h_inhibition label: PDE6H inhibitory gamma subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PDE6H term: id: UniProtKB:Q13956 label: Retinal cone rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma function: preferred_term: enzyme inhibitor activity term: id: GO:0004857 label: enzyme inhibitor activity targets: - preferred_term: PDE6C term: id: UniProtKB:P51160 label: Cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha' processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: cone photoreceptor disc membrane term: id: GO:0120201 label: cone photoreceptor disc membrane role_description: >- Keeps cone PDE6 inactive in darkness; displaced by GTP-bound GNAT2. evidence: - source_id: PMID:20940301 statement: Rod and cone gamma subunits inhibit PDE6 with comparable potency. supporting_text: Likewise, the K(i) values for PDE6C, PDE6C-A, and PDE6C-B inhibition by the cone- and rod-specific PDE6 γ-subunits (Pγ) were comparable. gocam_associations: - model: gomodel:68fac5ed00003872 activity: gomodel:68fac5ed00003872/69ea894900000222 title: PDE6H enzyme inhibitor activity (GO:0004857), OPN1LW model description: Same gene and molecular function; inhibits PDE6C in that model. - model: gomodel:69ea894900003713 activity: gomodel:69ea894900003713/69ea894900003739 title: PDE6H enzyme inhibitor activity (GO:0004857), OPN1SW model - model: gomodel:69ea894900003563 activity: gomodel:69ea894900003563/69ea894900003589 title: PDE6H enzyme inhibitor activity (GO:0004857), OPN1MW model - order: 4 role: CNG channel closure (dark current suppression) node: id: phototransduction_cng_channel label: cGMP-gated channel closure module_type: TRANSPORT_STEP description: >- cGMP holds the outer-segment CNG channels open in darkness, carrying an inward Na+/Ca2+ current. The light-induced fall in cGMP closes them and the cell hyperpolarises. variant_sets: - id: cng_cell_type label: Rod and cone CNG channels axis: photoreceptor cell type selection: ONE_OR_MORE variants: - id: rod_cng label: Rod CNG channel (CNGA1/CNGB1) module_type: TRANSPORT_STEP annotons: - id: rod_cng_activity label: Rod CNGA1/CNGB1 cGMP-activated cation channel participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: rod CNG channel (3 CNGA1 + 1 CNGB1) term: id: GO:0017071 label: intracellular cyclic nucleotide activated cation channel complex active_units: - id: cnga1_unit label: CNGA1 subunit role: Principal cGMP-binding and pore-forming subunit. stoichiometry: '3' participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CNGA1 term: id: UniProtKB:P29973 label: Cyclic nucleotide-gated channel alpha-1 - id: cngb1_unit label: CNGB1 subunit role: Modulatory subunit conferring native gating and pharmacology. stoichiometry: '1' participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CNGB1 term: id: UniProtKB:Q14028 label: Cyclic nucleotide-gated channel beta-1 function: preferred_term: intracellularly cGMP-activated cation channel activity term: id: GO:0005223 label: intracellularly cGMP-activated cation channel activity processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: photoreceptor outer segment membrane term: id: GO:0042622 label: photoreceptor outer segment membrane role_description: Carries the rod dark current; closes when cGMP falls. evidence: - source_id: PMID:34699778 statement: The native rod channel is a 3:1 CNGA1/CNGB1 heterotetramer. supporting_text: the native rod CNG functions as a heterotetramer consisting of three A1 and one B1 subunits - source_id: file:human/CNGA1/CNGA1-ai-review.yaml statement: Matches the completed human CNGA1 review (contributes_to GO:0005223). - source_id: file:human/CNGB1/CNGB1-ai-review.yaml statement: Matches the completed human CNGB1 review. gocam_associations: - model: gomodel:6918f23700000035 activity: gomodel:6918f23700000035/69ea894900004226 title: CNGA1/CNGB1 channel complex intracellularly cGMP-activated cation channel activity (GO:0005223) description: Same complex and molecular function; terminal activity of the rod model. - id: cone_cng label: Cone CNG channel (CNGA3/CNGB3) module_type: TRANSPORT_STEP annotons: - id: cone_cng_activity label: Cone CNGA3/CNGB3 cGMP-activated cation channel participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: cone CNG channel (CNGA3 + CNGB3) term: id: GO:0017071 label: intracellular cyclic nucleotide activated cation channel complex active_units: - id: cnga3_unit label: CNGA3 subunit role: Principal cGMP-binding and pore-forming subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CNGA3 term: id: UniProtKB:Q16281 label: Cyclic nucleotide-gated channel alpha-3 - id: cngb3_unit label: CNGB3 subunit role: Modulatory subunit tuning ligand sensitivity and pore properties. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CNGB3 term: id: UniProtKB:Q9NQW8 label: Cyclic nucleotide-gated channel beta-3 function: preferred_term: intracellularly cGMP-activated cation channel activity term: id: GO:0005223 label: intracellularly cGMP-activated cation channel activity processes: - preferred_term: transducin-mediated opsin signaling pathway term: id: GO:0141190 label: transducin-mediated opsin signaling pathway locations: - preferred_term: photoreceptor outer segment membrane term: id: GO:0042622 label: photoreceptor outer segment membrane role_description: Carries the cone dark current; mutated in achromatopsia. evidence: - source_id: PMID:12815043 statement: The cone channel is a CNGA3/CNGB3 heteromer. supporting_text: Cone photoreceptor cyclic nucleotide-gated (CNG) channels are thought to form by assembly of two different subunit types, CNGA3 and CNGB3. - source_id: file:human/CNGA3/CNGA3-ai-review.yaml statement: Matches the completed human CNGA3 review (contributes_to GO:0005223). - source_id: file:human/CNGB3/CNGB3-ai-review.yaml statement: Matches the completed human CNGB3 review (contributes_to GO:0005223). gocam_associations: - model: gomodel:68fac5ed00003872 activity: gomodel:68fac5ed00003872/69ea894900003340 title: CNGA3/CNGB3 channel complex intracellularly cGMP-activated cation channel activity (GO:0005223), OPN1LW model - model: gomodel:69ea894900003713 activity: gomodel:69ea894900003713/69ea894900003762 title: CNGA3/CNGB3 channel complex activity (GO:0005223), OPN1SW model - model: gomodel:69ea894900003563 activity: gomodel:69ea894900003563/69ea894900003612 title: CNGA3/CNGB3 channel complex activity (GO:0005223), OPN1MW model - order: 5 role: outer-segment Ca2+ extrusion node: id: phototransduction_nckx label: Na+/Ca2+,K+ exchange module_type: TRANSPORT_STEP description: >- The K+-dependent Na+/Ca2+ exchanger extrudes the Ca2+ that enters through CNG channels. When the channels close it keeps extruding, so outer-segment Ca2+ falls, which is the signal for the Ca2+-feedback steps of recovery. variant_sets: - id: nckx_cell_type label: Rod and cone NCKX axis: photoreceptor cell type selection: ONE_OR_MORE variants: - id: rod_nckx label: Rod NCKX1 (SLC24A1) module_type: TRANSPORT_STEP annotons: - id: slc24a1_exchange label: SLC24A1 calcium, potassium:sodium antiporter activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SLC24A1 (NCKX1) term: id: UniProtKB:O60721 label: Sodium/potassium/calcium exchanger 1 function: preferred_term: calcium, potassium:sodium antiporter activity term: id: GO:0008273 label: calcium, potassium:sodium antiporter activity processes: - preferred_term: calcium ion transmembrane transport term: id: GO:0070588 label: calcium ion transmembrane transport locations: - preferred_term: photoreceptor outer segment membrane term: id: GO:0042622 label: photoreceptor outer segment membrane role_description: Rod outer-segment Ca2+ extrusion. evidence: - source_id: PMID:10662833 statement: The rod outer-segment exchanger is an NCKX. supporting_text: The Na-Ca exchanger in retinal rod outer segment was shown earlier to be a novel Na-Ca+K exchanger (NCKX) - id: cone_nckx label: Cone NCKX2 (SLC24A2) module_type: TRANSPORT_STEP annotons: - id: slc24a2_exchange label: SLC24A2 calcium, potassium:sodium antiporter activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SLC24A2 (NCKX2) term: id: UniProtKB:Q9UI40 label: Sodium/potassium/calcium exchanger 2 function: preferred_term: calcium, potassium:sodium antiporter activity term: id: GO:0008273 label: calcium, potassium:sodium antiporter activity processes: - preferred_term: calcium ion transmembrane transport term: id: GO:0070588 label: calcium ion transmembrane transport locations: - preferred_term: photoreceptor outer segment membrane term: id: GO:0042622 label: photoreceptor outer segment membrane role_description: Cone outer-segment Ca2+ extrusion. evidence: - source_id: PMID:10662833 statement: Human cone NCKX shows K+-dependent Na-Ca exchange activity. supporting_text: We identified NCKX transcripts in both human and chicken cones and observed strong potassium-dependent Na-Ca exchange activity after heterologous expression of human and chicken cone NCKX cDNAs in cultured insect cells. - order: 6 role: opsin phosphorylation node: id: phototransduction_opsin_phosphorylation label: Opsin phosphorylation by rhodopsin kinase module_type: REGULATORY_STEP description: >- Rhodopsin kinase phosphorylates the C-terminal tail of the photoactivated opsin, reducing its activity and preparing it for arrestin binding. variant_sets: - id: opsin_kinase label: Rhodopsin kinases axis: kinase paralog selection: ONE_OR_MORE notes: >- Axis is the kinase rather than cell type: rods use GRK1, while human cones express GRK1 and GRK7. variants: - id: grk1_variant label: GRK1 (rods and cones) module_type: REGULATORY_STEP annotons: - id: grk1_kinase label: GRK1 rhodopsin kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK1 term: id: UniProtKB:Q15835 label: Rhodopsin kinase GRK1 function: preferred_term: rhodopsin kinase activity term: id: GO:0050254 label: rhodopsin kinase activity substrates: - preferred_term: photoactivated rhodopsin term: id: UniProtKB:P08100 label: Rhodopsin processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: photoreceptor outer segment term: id: GO:0001750 label: photoreceptor outer segment role_description: >- Required for prompt rhodopsin shut-off; GRK1 deficiency causes Oguchi disease. evidence: - source_id: PMID:10097103 statement: >- Loss of rhodopsin kinase abolishes light-dependent rhodopsin phosphorylation and prolongs the single-photon response. supporting_text: This eliminated the light-dependent phosphorylation of rhodopsin and caused the single-photon response to become larger and longer lasting than normal. - source_id: PMID:15946941 statement: GRK1 phosphorylates rhodopsin in rods. supporting_text: In rod cells of the vertebrate retina, phosphorylation of rhodopsin is mediated by GRK1. - id: grk7_variant label: GRK7 (cones) module_type: REGULATORY_STEP annotons: - id: grk7_kinase label: GRK7 rhodopsin kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK7 term: id: UniProtKB:Q8WTQ7 label: Rhodopsin kinase GRK7 function: preferred_term: rhodopsin kinase activity term: id: GO:0050254 label: rhodopsin kinase activity substrates: - preferred_term: photoactivated cone opsins processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: cone photoreceptor outer segment term: id: GO:0120199 label: cone photoreceptor outer segment role_description: Cone opsin kinase with kinetic properties similar to GRK1. evidence: - source_id: PMID:15946941 statement: GRK1 and/or GRK7 phosphorylate cone opsins, depending on species. supporting_text: In cone cells, either GRK1, GRK7, or both, depending on the species, are speculated to initiate signal termination by phosphorylating the cone opsins. - order: 7 role: arrestin capping of phosphorylated opsin node: id: phototransduction_arrestin label: Arrestin binding to phosphorylated opsin module_type: REGULATORY_STEP description: >- Arrestin binds the phosphorylated, photoactivated opsin and blocks its interaction with transducin, completing pigment shut-off. variant_sets: - id: arrestin_cell_type label: Rod and cone arrestins axis: photoreceptor cell type selection: ONE_OR_MORE notes: SAG is also expressed in cones, alongside ARR3. variants: - id: rod_arrestin label: Rod arrestin (SAG) module_type: REGULATORY_STEP annotons: - id: sag_receptor_inhibition label: SAG (S-arrestin) opsin inhibition participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SAG (rod arrestin) term: id: UniProtKB:P10523 label: S-arrestin function: preferred_term: signaling receptor inhibitor activity term: id: GO:0030547 label: signaling receptor inhibitor activity targets: - preferred_term: phosphorylated rhodopsin term: id: UniProtKB:P08100 label: Rhodopsin processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: photoreceptor outer segment term: id: GO:0001750 label: photoreceptor outer segment role_description: >- Completes the quench of rhodopsin activity after phosphorylation; SAG loss causes Oguchi disease. evidence: - source_id: PMID:9333241 statement: Arrestin completes the quench of rhodopsin's catalytic activity in intact rods. supporting_text: This behaviour indicates that an arrestin-independent mechanism initiates the quench of rhodopsin's catalytic activity and that arrestin completes the quench. - source_id: PMID:26200343 statement: Arrestin binding to the receptor blocks G protein interaction. supporting_text: Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. - id: cone_arrestin label: Cone arrestin (ARR3) module_type: REGULATORY_STEP annotons: - id: arr3_receptor_inhibition label: ARR3 (cone arrestin) opsin inhibition participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ARR3 (cone arrestin) term: id: UniProtKB:P36575 label: Arrestin-C function: preferred_term: signaling receptor inhibitor activity term: id: GO:0030547 label: signaling receptor inhibitor activity targets: - preferred_term: phosphorylated cone opsins processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: cone photoreceptor outer segment term: id: GO:0120199 label: cone photoreceptor outer segment role_description: >- Cone-specific arrestin; by homology with SAG it caps phosphorylated cone opsins. notes: >- No cached primary paper on ARR3 was used; the role rests on family membership and the RGD diagram, and its GOA molecular functions are IBA/ISS/IEA (GPCR binding, opsin binding, protein sequestering). - order: 8 role: Ca2+-dependent control of opsin phosphorylation node: id: phototransduction_recoverin label: Recoverin inhibition of rhodopsin kinase module_type: REGULATORY_STEP description: >- At the high Ca2+ of darkness, Ca2+-recoverin binds and inhibits rhodopsin kinase. The light-induced fall in Ca2+ releases the kinase and shortens the lifetime of active opsin, a component of light adaptation. annotons: - id: rcvrn_kinase_inhibition label: Recoverin (RCVRN) Ca2+-dependent rhodopsin kinase inhibition participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RCVRN (recoverin, S-modulin) term: id: UniProtKB:P35243 label: Recoverin function: preferred_term: protein kinase inhibitor activity term: id: GO:0004860 label: protein kinase inhibitor activity targets: - preferred_term: GRK1 term: id: UniProtKB:Q15835 label: Rhodopsin kinase GRK1 processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: photoreceptor outer segment term: id: GO:0001750 label: photoreceptor outer segment role_description: Ca2+ sensor coupling the light-induced Ca2+ fall to faster opsin shut-off. evidence: - source_id: PMID:8386803 statement: >- Recoverin (S-modulin) inhibits rhodopsin phosphorylation at high Ca2+, prolonging PDE activity. supporting_text: At the high Ca2+ concentrations at which S-modulin prolongs the lifetime of PDE*, S-modulin inhibits rhodopsin phosphorylation - order: 9 role: transducin inactivation node: id: phototransduction_rgs9_gap label: RGS9 GAP complex acceleration of transducin GTPase module_type: REGULATORY_STEP description: >- The membrane-anchored RGS9-1/GNB5L/RGS9BP complex accelerates GTP hydrolysis by transducin alpha, switching off transducin and with it PDE6. annotons: - id: rgs9_gap_activity label: RGS9-1/GNB5/RGS9BP GTPase activator activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: RGS9-1/GNB5L/RGS9BP transducin GAP complex active_units: - id: rgs9_unit label: RGS9-1 role: Catalytic RGS domain that stimulates transducin alpha GTPase. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS9 (RGS9-1 isoform) term: id: UniProtKB:O75916 label: Regulator of G protein signaling 9 - id: gnb5_unit label: GNB5 (long isoform Gbeta5L) role: Obligate partner of RGS9-1 through its G gamma-like domain. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNB5 term: id: UniProtKB:O14775 label: Guanine nucleotide-binding protein subunit beta-5 - id: rgs9bp_unit label: RGS9BP (R9AP) role: Transmembrane anchor that targets the complex to disc membranes and enhances RGS9 activity. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS9BP (R9AP) term: id: UniProtKB:Q6ZS82 label: Regulator of G protein signaling 9-binding protein function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: GNAT1 (rod transducin alpha) term: id: UniProtKB:P11488 label: Guanine nucleotide-binding protein G(t) subunit alpha-1 - preferred_term: GNAT2 (cone transducin alpha) term: id: UniProtKB:P19087 label: Guanine nucleotide-binding protein G(t) subunit alpha-2 processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: photoreceptor disc membrane term: id: GO:0097381 label: photoreceptor disc membrane role_description: >- Deactivates rod and cone transducins; loss of RGS9 or RGS9BP causes bradyopsia. evidence: - source_id: PMID:10051575 statement: Photoreceptor RGS9 exists as a tight complex with Gbeta5L. supporting_text: functionally active RGS9 from vertebrate photoreceptors exists as a tight complex with the long splice variant of the G protein beta subunit (Gbeta5L) - source_id: PMID:14702087 statement: RGS9 deactivates rod and cone transducins. supporting_text: RGS9 deactivates the G proteins (transducins) in the rod and cone phototransduction cascades. - source_id: PMID:14702087 statement: R9AP anchors RGS9 and strongly enhances its activity. supporting_text: It is anchored to photoreceptor membranes by the transmembrane protein R9AP (RGS9 anchor protein), which enhances RGS9 activity up to 70-fold. - order: 10 role: Ca2+-feedback cGMP resynthesis node: id: phototransduction_cgmp_resynthesis label: GCAP-stimulated retGC cGMP synthesis module_type: REACTION description: >- The retinal membrane guanylate cyclases synthesise cGMP. They are stimulated by Ca2+-free GCAPs, so the light-induced fall in Ca2+ accelerates cGMP resynthesis and channel reopening. annotons: - id: retgc_cyclase label: Retinal guanylate cyclase activity (GUCY2D/GUCY2F) participant: selector_type: FAMILY family: preferred_term: retinal membrane guanylate cyclases (RetGC1/RetGC2) representative_members: - preferred_term: GUCY2D (RetGC1; rodent Gucy2e) term: id: UniProtKB:Q02846 label: Retinal guanylyl cyclase 1 - preferred_term: GUCY2F (RetGC2) term: id: UniProtKB:P51841 label: Retinal guanylyl cyclase 2 function: preferred_term: guanylate cyclase activity term: id: GO:0004383 label: guanylate cyclase activity substrates: - preferred_term: GTP products: - preferred_term: 3',5'-cyclic GMP - preferred_term: diphosphate processes: - preferred_term: cGMP biosynthetic process term: id: GO:0006182 label: cGMP biosynthetic process - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: photoreceptor disc membrane term: id: GO:0097381 label: photoreceptor disc membrane role_description: >- Resynthesises cGMP; GUCY2D (RetGC1) is the dominant isoform, and its loss causes Leber congenital amaurosis. evidence: - source_id: PMID:9702199 statement: GCAP1 stimulates the photoreceptor guanylate cyclase GC1. supporting_text: We show that the GCAP1(Y99C) mutant and native GCAP1 are highly effective in stimulation of photoreceptor GC1. - id: gcap_activation label: GCAP1/GCAP2 calcium sensitive guanylate cyclase activator activity participant: selector_type: FAMILY family: preferred_term: guanylate cyclase-activating proteins (GCAP1/GCAP2) representative_members: - preferred_term: GUCA1A (GCAP1) term: id: UniProtKB:P43080 label: Guanylyl cyclase-activating protein 1 - preferred_term: GUCA1B (GCAP2) term: id: UniProtKB:Q9UMX6 label: Guanylyl cyclase-activating protein 2 function: preferred_term: calcium sensitive guanylate cyclase activator activity term: id: GO:0008048 label: calcium sensitive guanylate cyclase activator activity targets: - preferred_term: GUCY2D (RetGC1) term: id: UniProtKB:Q02846 label: Retinal guanylyl cyclase 1 - preferred_term: GUCY2F (RetGC2) term: id: UniProtKB:P51841 label: Retinal guanylyl cyclase 2 processes: - preferred_term: photoresponse recovery term: id: GO:0036368 label: photoresponse recovery locations: - preferred_term: photoreceptor outer segment term: id: GO:0001750 label: photoreceptor outer segment role_description: >- Ca2+ sensors that activate retGC when Ca2+ falls and inhibit it in darkness. GUCA1A was added to the RGD gene list (see module notes). evidence: - source_id: PMID:9702199 statement: GCAP1 stimulates retGC at low Ca2+ and is inactivated at high Ca2+. supporting_text: GCAP1 stimulates photoreceptor guanylate cyclase (GC) in bleached vertebrate photoreceptors when [Ca2+]free decreases but is inactivated when cytoplasmic [Ca2+]free increase after dark adaptation. - source_id: PMID:11493703 statement: GCAPs confer the Ca2+ dependence of retinal GC activity in vivo. supporting_text: The GC activity from GCAPs-/- retinas showed no Ca(2+) dependence, indicating that Ca(2+) regulation of GCs had indeed been abolished. - order: 11 role: chromophore regeneration node: id: phototransduction_chromophore_regeneration label: Retinoid visual cycle module_ref: retinoid_visual_cycle description: >- Regenerates the 11-cis-retinal released from bleached opsins; drawn by RGD as the subpathway PW:0001005 and modelled as a separate module. connections: - source: phototransduction_chromophore_regeneration target: phototransduction_photon_capture connection_type: PROVIDES_INPUT_FOR description: The visual cycle supplies 11-cis-retinal to regenerate the visual pigment. - source: phototransduction_photon_capture target: phototransduction_transducin connection_type: POSITIVELY_REGULATES description: Photoactivated opsin catalyses GDP/GTP exchange on transducin alpha. - source: phototransduction_transducin target: phototransduction_pde6 connection_type: POSITIVELY_REGULATES description: >- GTP-bound transducin alpha binds the PDE6 gamma subunits and relieves their inhibition of the catalytic subunits. - source: phototransduction_pde6 target: phototransduction_cng_channel connection_type: NEGATIVELY_REGULATES description: PDE6 hydrolyses the cGMP that holds the CNG channels open. - source: phototransduction_cng_channel target: phototransduction_nckx connection_type: PROVIDES_INPUT_FOR description: >- Ca2+ entering through open CNG channels is extruded by NCKX; channel closure with continued extrusion lowers outer-segment Ca2+. - source: phototransduction_cng_channel target: phototransduction_recoverin connection_type: POSITIVELY_REGULATES description: >- Ca2+ entering through open CNG channels in darkness keeps recoverin in its Ca2+-bound, kinase-inhibiting form. - source: phototransduction_nckx target: phototransduction_recoverin connection_type: NEGATIVELY_REGULATES description: >- Continued Ca2+ extrusion after channel closure lowers Ca2+ and releases recoverin from rhodopsin kinase. - source: phototransduction_cng_channel target: phototransduction_cgmp_resynthesis connection_type: NEGATIVELY_REGULATES description: >- Ca2+ entering through open CNG channels keeps GCAPs in their Ca2+-bound form, which does not stimulate retGC. - source: phototransduction_nckx target: phototransduction_cgmp_resynthesis connection_type: POSITIVELY_REGULATES description: >- The light-induced Ca2+ fall produced by NCKX extrusion converts GCAPs to their Ca2+-free, retGC-stimulating form. - source: phototransduction_opsin_phosphorylation target: phototransduction_photon_capture connection_type: NEGATIVELY_REGULATES description: Phosphorylation reduces the activity of the photoactivated opsin. - source: phototransduction_opsin_phosphorylation target: phototransduction_arrestin connection_type: PRECEDES description: Arrestin binds the phosphorylated opsin. - source: phototransduction_arrestin target: phototransduction_photon_capture connection_type: NEGATIVELY_REGULATES description: Arrestin caps the phosphorylated opsin and blocks transducin activation. - source: phototransduction_recoverin target: phototransduction_opsin_phosphorylation connection_type: NEGATIVELY_REGULATES description: Ca2+-recoverin inhibits rhodopsin kinase in darkness; the light-induced Ca2+ fall relieves it. - source: phototransduction_rgs9_gap target: phototransduction_transducin connection_type: NEGATIVELY_REGULATES description: The RGS9 complex accelerates GTP hydrolysis by transducin alpha. - source: phototransduction_cgmp_resynthesis target: phototransduction_cng_channel connection_type: POSITIVELY_REGULATES description: Resynthesised cGMP reopens the CNG channels.