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

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.

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.