Visual phototransduction (Homo sapiens)

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Description

Visual phototransduction is the process by which photon absorption by visual pigment molecules in photoreceptor cells is converted to an electrical cellular response. The events in this process are photochemical, biochemical and electrophysiological and are highly conserved across many species. This process occurs in two types of photoreceptors in the retina, rods and cones. Each type consists of two parts, the outer segment which detects a photon signal and the inner segment which contains the necessary machinery for cell metabolism. Each type of cell functions differently. Rods are very light sensitive but their flash response is slow so they work best in twilight conditions but are not good at detecting objects moving quickly. Cones are less light-sensitive and have a fast flash response so they work best in daylight conditions and are better at detecting fast moving objects than rods.

The visual pigment consists of a chromophore (11-cis-retinal, 11cRAL, A1) covalently attached to a GPCR opsin family member. The linkage is via a Schiff base forming retinylidene protein. Upon photon absorption, 11cRAL isomerises to all-trans retinal (atRAL), changing the conformation of opsin to an activated form which can activate the regulatory G protein transducin (Gt). The alpha subunit of Gt activates phosphodiesterase which hydrolyses cGMP to 5'-GMP. As high level of cGMP keep cGMP-gated sodium channels open, the lowering of cGMP levels closes these channels which causes hyperpolarization of the cell and subsequently, closure of voltage-gated calcium channels. As calcium levels drop, the level of the neurotransmitter glutamate also drops causing depolarization of the cell. This effectively relays the light signal to postsynaptic neurons as electrical signal (Burns & Pugh 2010, Korenbrot 2012, Pugh & Lamb 1993).

11cRAL cannot be synthesised in vertebrates. Vitamin A from many dietary sources is the precursor for 11cRAL. It is taken from food in the form of esters such as retinyl acetate or palmitate or one of four caretenoids (alpha-carotene, beta-carotene, gamma-carotene and beta-cryptoxanthin). Retinoids are transported from the gut to be stored in liver, until required by target organs such as the eye (Harrison & Hussain 2001, Harrison 2005). In the eye, in the form 11cRAL, it is used in the retinoid (visual) cycle to initiate phototransduction and for visual pigment regeneration to ready the photoreceptor for the next phototransduction event (von Lintig 2012, Blomhoff & Blomhoff 2006, von Lintig et al. 2010, D'Ambrosio et al. 2011, Wang & Kefalov 2011, Kefalov 2012, Wolf 2004). View original pathway at Reactome.

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Pathway is converted from Reactome ID: 2187338
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Reactome version: 75
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Reactome Author: Jassal, Bijay

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  98. Lopes VS, Gibbs D, Libby RT, Aleman TS, Welch DL, Lillo C, Jacobson SG, Radu RA, Steel KP, Williams DS.; ''The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65.''; PubMed Europe PMC Scholia
  99. Premont RT, Macrae AD, Stoffel RH, Chung N, Pitcher JA, Ambrose C, Inglese J, MacDonald ME, Lefkowitz RJ.; ''Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants.''; PubMed Europe PMC Scholia
  100. Ueda N, Okamoto Y, Morishita J.; ''N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: a novel enzyme of the beta-lactamase fold family releasing anandamide and other N-acylethanolamines.''; PubMed Europe PMC Scholia
  101. Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Shy Chen M, Alan Lewis R, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev YV, Hejtmancik JF.; ''Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2.''; PubMed Europe PMC Scholia
  102. Kaylor JJ, Yuan Q, Cook J, Sarfare S, Makshanoff J, Miu A, Kim A, Kim P, Habib S, Roybal CN, Xu T, Nusinowitz S, Travis GH.; ''Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina.''; PubMed Europe PMC Scholia
  103. Hsu YT, Molday RS.; ''Interaction of calmodulin with the cyclic GMP-gated channel of rod photoreceptor cells. Modulation of activity, affinity purification, and localization.''; PubMed Europe PMC Scholia
  104. Fan G, Siebert F, Sheves M, Vogel R.; ''Rhodopsin with 11-cis-locked chromophore is capable of forming an active state photoproduct.''; PubMed Europe PMC Scholia
  105. Pittler SJ, Baehr W, Wasmuth JJ, McConnell DG, Champagne MS, vanTuinen P, Ledbetter D, Davis RL.; ''Molecular characterization of human and bovine rod photoreceptor cGMP phosphodiesterase alpha-subunit and chromosomal localization of the human gene.''; PubMed Europe PMC Scholia
  106. Kutuzov MA, Bennett N.; ''Calcium-activated opsin phosphatase activity in retinal rod outer segments.''; PubMed Europe PMC Scholia
  107. Murakami A, Yajima T, Inana G.; ''Isolation of human retinal genes: recoverin cDNA and gene.''; PubMed Europe PMC Scholia
  108. Simon A, Lagercrantz J, Bajalica-Lagercrantz S, Eriksson U.; ''Primary structure of human 11-cis retinol dehydrogenase and organization and chromosomal localization of the corresponding gene.''; PubMed Europe PMC Scholia
  109. Michaelides M, Li Z, Rana NA, Richardson EC, Hykin PG, Moore AT, Holder GE, Webster AR.; ''Novel mutations and electrophysiologic findings in RGS9- and R9AP-associated retinal dysfunction (Bradyopsia).''; PubMed Europe PMC Scholia
  110. Wu BX, Chen Y, Chen Y, Fan J, Rohrer B, Crouch RK, Ma JX.; ''Cloning and characterization of a novel all-trans retinol short-chain dehydrogenase/reductase from the RPE.''; PubMed Europe PMC Scholia
  111. Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH.; ''Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease.''; PubMed Europe PMC Scholia
  112. Fesenko EE, Kolesnikov SS, Lyubarsky AL.; ''Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment.''; PubMed Europe PMC Scholia
  113. Intres R, Goldflam S, Cook JR, Crabb JW.; ''Molecular cloning and structural analysis of the human gene encoding cellular retinaldehyde-binding protein.''; PubMed Europe PMC Scholia
  114. Rattner A, Smallwood PM, Nathans J.; ''Identification and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol.''; PubMed Europe PMC Scholia
  115. Kokame K, Fukada Y, Yoshizawa T, Takao T, Shimonishi Y.; ''Lipid modification at the N terminus of photoreceptor G-protein alpha-subunit.''; PubMed Europe PMC Scholia
  116. Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A.; ''A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.''; PubMed Europe PMC Scholia
  117. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N.; ''Molecular characterization of a phospholipase D generating anandamide and its congeners.''; PubMed Europe PMC Scholia
  118. Hofmann KP.; ''Effect of GTP on the rhodopsin-G-protein complex by transient formation of extra metarhodopsin II.''; PubMed Europe PMC Scholia
  119. Fong SL, Bridges CD.; ''Internal quadruplication in the structure of human interstitial retinol-binding protein deduced from its cloned cDNA.''; PubMed Europe PMC Scholia
  120. Nakatani K, Yau KW.; ''Calcium and magnesium fluxes across the plasma membrane of the toad rod outer segment.''; PubMed Europe PMC Scholia
  121. Wolf G.; ''The visual cycle of the cone photoreceptors of the retina.''; PubMed Europe PMC Scholia
  122. Beharry S, Zhong M, Molday RS.; ''N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR).''; PubMed Europe PMC Scholia
  123. Baylor DA, Nunn BJ.; ''Electrical properties of the light-sensitive conductance of rods of the salamander Ambystoma tigrinum.''; PubMed Europe PMC Scholia
  124. Fowles C, Akhtar M, Cohen P.; ''Interplay of phosphorylation and dephosphorylation in vision: protein phosphatases of bovine rod outer segments.''; PubMed Europe PMC Scholia
  125. Sparrow JR, Fishkin N, Zhou J, Cai B, Jang YP, Krane S, Itagaki Y, Nakanishi K.; ''A2E, a byproduct of the visual cycle.''; PubMed Europe PMC Scholia
  126. Nishiguchi KM, Sandberg MA, Kooijman AC, Martemyanov KA, Pott JW, Hagstrom SA, Arshavsky VY, Berson EL, Dryja TP.; ''Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation.''; PubMed Europe PMC Scholia
  127. Fung BK, Hurley JB, Stryer L.; ''Flow of information in the light-triggered cyclic nucleotide cascade of vision.''; PubMed Europe PMC Scholia
  128. Zhang K, Howes KA, He W, Bronson JD, Pettenati MJ, Chen C, Palczewski K, Wensel TG, Baehr W.; ''Structure, alternative splicing, and expression of the human RGS9 gene.''; PubMed Europe PMC Scholia
  129. Hsu YT, Molday RS.; ''Modulation of the cGMP-gated channel of rod photoreceptor cells by calmodulin.''; PubMed Europe PMC Scholia
  130. Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H.; ''A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A.''; PubMed Europe PMC Scholia
  131. Surguchov A, Bronson JD, Banerjee P, Knowles JA, Ruiz C, Subbaraya I, Palczewski K, Baehr W.; ''The human GCAP1 and GCAP2 genes are arranged in a tail-to-tail array on the short arm of chromosome 6 (p21.1).''; PubMed Europe PMC Scholia
  132. Folli C, Calderone V, Ottonello S, Bolchi A, Zanotti G, Stoppini M, Berni R.; ''Identification, retinoid binding, and x-ray analysis of a human retinol-binding protein.''; PubMed Europe PMC Scholia
  133. Osawa S, Jo R, Weiss ER.; ''Phosphorylation of GRK7 by PKA in cone photoreceptor cells is regulated by light.''; PubMed Europe PMC Scholia
  134. Cheng JB, Russell DW.; ''Mammalian wax biosynthesis. II. Expression cloning of wax synthase cDNAs encoding a member of the acyltransferase enzyme family.''; PubMed Europe PMC Scholia
  135. Young RW.; ''The renewal of photoreceptor cell outer segments.''; PubMed Europe PMC Scholia
  136. Kiser PD, Golczak M, Palczewski K.; ''Chemistry of the retinoid (visual) cycle.''; PubMed Europe PMC Scholia
  137. Yau KW, Baylor DA.; ''Cyclic GMP-activated conductance of retinal photoreceptor cells.''; PubMed Europe PMC Scholia
  138. Sokal I, Hu G, Liang Y, Mao M, Wensel TG, Palczewski K.; ''Identification of protein kinase C isozymes responsible for the phosphorylation of photoreceptor-specific RGS9-1 at Ser475.''; PubMed Europe PMC Scholia
  139. Hargrave PA, McDowell JH, Curtis DR, Wang JK, Juszczak E, Fong SL, Rao JK, Argos P.; ''The structure of bovine rhodopsin.''; PubMed Europe PMC Scholia
  140. Riazuddin SA, Shahzadi A, Zeitz C, Ahmed ZM, Ayyagari R, Chavali VR, Ponferrada VG, Audo I, Michiels C, Lancelot ME, Nasir IA, Zafar AU, Khan SN, Husnain T, Jiao X, MacDonald IM, Riazuddin S, Sieving PA, Katsanis N, Hejtmancik JF.; ''A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness.''; PubMed Europe PMC Scholia
  141. Marino JP, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK.; ''Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore.''; PubMed Europe PMC Scholia
  142. Van Dop C, Medynski DC, Apone LM.; ''Nucleotide sequence for a cDNA encoding the alpha subunit of retinal transducin (GNAT1) isolated from the human eye.''; PubMed Europe PMC Scholia
  143. Nathans J, Hogness DS.; ''Isolation and nucleotide sequence of the gene encoding human rhodopsin.''; PubMed Europe PMC Scholia
  144. Fong SL.; ''Characterization of the human rod transducin alpha-subunit gene.''; PubMed Europe PMC Scholia
  145. Arne JM, Widjaja-Adhi MA, Hughes T, Huynh KW, Silvaroli JA, Chelstowska S, Moiseenkova-Bell VY, Golczak M.; ''Allosteric modulation of the substrate specificity of acyl-CoA wax alcohol acyltransferase 2.''; PubMed Europe PMC Scholia
  146. Tsybovsky Y, Molday RS, Palczewski K.; ''The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease.''; PubMed Europe PMC Scholia
  147. Wang J, Okamoto Y, Morishita J, Tsuboi K, Miyatake A, Ueda N.; ''Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-beta-lactamase family.''; PubMed Europe PMC Scholia
  148. Weitz D, Ficek N, Kremmer E, Bauer PJ, Kaupp UB.; ''Subunit stoichiometry of the CNG channel of rod photoreceptors.''; PubMed Europe PMC Scholia
  149. Young RW, Bok D.; ''Participation of the retinal pigment epithelium in the rod outer segment renewal process.''; PubMed Europe PMC Scholia
  150. Pugh EN, Lamb TD.; ''Amplification and kinetics of the activation steps in phototransduction.''; PubMed Europe PMC Scholia
  151. Shyjan AW, de Sauvage FJ, Gillett NA, Goeddel DV, Lowe DG.; ''Molecular cloning of a retina-specific membrane guanylyl cyclase.''; PubMed Europe PMC Scholia
  152. Wensel TG, Stryer L.; ''Reciprocal control of retinal rod cyclic GMP phosphodiesterase by its gamma subunit and transducin.''; PubMed Europe PMC Scholia
  153. Ramulu P, Kennedy M, Xiong WH, Williams J, Cowan M, Blesh D, Yau KW, Hurley JB, Nathans J.; ''Normal light response, photoreceptor integrity, and rhodopsin dephosphorylation in mice lacking both protein phosphatases with EF hands (PPEF-1 and PPEF-2).''; PubMed Europe PMC Scholia
  154. Crabb JW, Carlson A, Chen Y, Goldflam S, Intres R, West KA, Hulmes JD, Kapron JT, Luck LA, Horwitz J, Bok D.; ''Structural and functional characterization of recombinant human cellular retinaldehyde-binding protein.''; PubMed Europe PMC Scholia
  155. Katz ML, Drea CM, Eldred GE, Hess HH, Robison WG.; ''Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium.''; PubMed Europe PMC Scholia
  156. Berry DC, O'Byrne SM, Vreeland AC, Blaner WS, Noy N.; ''Cross talk between signaling and vitamin A transport by the retinol-binding protein receptor STRA6.''; PubMed Europe PMC Scholia
  157. Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS.; ''The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.''; PubMed Europe PMC Scholia
  158. Glover CJ, Hartman KD, Felsted RL.; ''Human N-myristoyltransferase amino-terminal domain involved in targeting the enzyme to the ribosomal subcellular fraction.''; PubMed Europe PMC Scholia
  159. Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow J.; ''Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium.''; PubMed Europe PMC Scholia
  160. Jones PG, Lombardi SJ, Cockett MI.; ''Cloning and tissue distribution of the human G protein beta 5 cDNA.''; PubMed Europe PMC Scholia
  161. Blomhoff R, Blomhoff HK.; ''Overview of retinoid metabolism and function.''; PubMed Europe PMC Scholia
  162. Belyaeva OV, Korkina OV, Stetsenko AV, Kim T, Nelson PS, Kedishvili NY.; ''Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids.''; PubMed Europe PMC Scholia
  163. Omer CA, Kral AM, Diehl RE, Prendergast GC, Powers S, Allen CM, Gibbs JB, Kohl NE.; ''Characterization of recombinant human farnesyl-protein transferase: cloning, expression, farnesyl diphosphate binding, and functional homology with yeast prenyl-protein transferases.''; PubMed Europe PMC Scholia
  164. Mata NL, Ruiz A, Radu RA, Bui TV, Travis GH.; ''Chicken retinas contain a retinoid isomerase activity that catalyzes the direct conversion of all-trans-retinol to 11-cis-retinol.''; PubMed Europe PMC Scholia
  165. Arfin SM, Kendall RL, Hall L, Weaver LH, Stewart AE, Matthews BW, Bradshaw RA.; ''Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent enzymes.''; PubMed Europe PMC Scholia
  166. Polans AS, Buczyłko J, Crabb J, Palczewski K.; ''A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy.''; PubMed Europe PMC Scholia
  167. Blakeley LR, Chen C, Chen CK, Chen J, Crouch RK, Travis GH, Koutalos Y.; ''Rod outer segment retinol formation is independent of Abca4, arrestin, rhodopsin kinase, and rhodopsin palmitylation.''; PubMed Europe PMC Scholia
  168. Rieke F, Baylor DA.; ''Molecular origin of continuous dark noise in rod photoreceptors.''; PubMed Europe PMC Scholia
  169. Tuteja N, Danciger M, Klisak I, Tuteja R, Inana G, Mohandas T, Sparkes RS, Farber DB.; ''Isolation and characterization of cDNA encoding the gamma-subunit of cGMP phosphodiesterase in human retina.''; PubMed Europe PMC Scholia
  170. Chassaing N, Golzio C, Odent S, Lequeux L, Vigouroux A, Martinovic-Bouriel J, Tiziano FD, Masini L, Piro F, Maragliano G, Delezoide AL, Attié-Bitach T, Manouvrier-Hanu S, Etchevers HC, Calvas P.; ''Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114665view16:13, 25 January 2021ReactomeTeamReactome version 75
113113view11:17, 2 November 2020ReactomeTeamReactome version 74
112347view15:27, 9 October 2020ReactomeTeamReactome version 73
101247view11:14, 1 November 2018ReactomeTeamreactome version 66
100786view20:41, 31 October 2018ReactomeTeamreactome version 65
100328view19:18, 31 October 2018ReactomeTeamreactome version 64
99874view16:01, 31 October 2018ReactomeTeamreactome version 63
99431view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99109view12:39, 31 October 2018ReactomeTeamreactome version 62
94030view13:52, 16 August 2017ReactomeTeamreactome version 61
93652view11:29, 9 August 2017ReactomeTeamreactome version 61
88350view16:18, 1 August 2016FehrhartOntology Term : 'photosignal transduction pathway' added !
86770view09:25, 11 July 2016ReactomeTeamreactome version 56
83212view10:24, 18 November 2015ReactomeTeamVersion54
81599view13:08, 21 August 2015ReactomeTeamVersion53
77056view08:35, 17 July 2014ReactomeTeamFixed remaining interactions
76761view12:12, 16 July 2014ReactomeTeamFixed remaining interactions
75146view14:09, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74793view08:53, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
11c-retinyl-RHOProteinP08100 (Uniprot-TrEMBL)
11c-retinyl-cone opsinsComplexR-HSA-2466099 (Reactome)
11cRAL MetaboliteCHEBI:16066 (ChEBI)
11cRAL-OPN1LW ProteinP04000 (Uniprot-TrEMBL)
11cRAL-OPN1LWProteinP04000 (Uniprot-TrEMBL)
11cRAL-OPN1MW ProteinP04001 (Uniprot-TrEMBL)
11cRAL-OPN1MWProteinP04001 (Uniprot-TrEMBL)
11cRAL-OPN1SW ProteinP03999 (Uniprot-TrEMBL)
11cRAL-OPN1SWProteinP03999 (Uniprot-TrEMBL)
11cRALMetaboliteCHEBI:16066 (ChEBI)
11cRDHR-HSA-2465962 (Reactome)
11cROL MetaboliteCHEBI:16302 (ChEBI)
11cROLMetaboliteCHEBI:16302 (ChEBI)
11cRPALM MetaboliteCHEBI:16254 (ChEBI)
11cRPALMMetaboliteCHEBI:16254 (ChEBI)
A2EMetaboliteCHEBI:71980 (ChEBI)
A2PEMetaboliteCHEBI:52592 (ChEBI)
ABCA4ProteinP78363 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
AWAT2ProteinQ6E213 (Uniprot-TrEMBL)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
C14:1-CoA MetaboliteCHEBI:70712 (ChEBI)
C14:2-CoA MetaboliteCHEBI:70713 (ChEBI)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1:Ca2+:CNG channelComplexR-HSA-3229184 (Reactome)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CAMKMTProteinQ7Z624 (Uniprot-TrEMBL)
CNG channelComplexR-HSA-74001 (Reactome)
CNGA1 ProteinP29973 (Uniprot-TrEMBL)
CNGB1 ProteinQ14028 (Uniprot-TrEMBL)
CYP4V2ProteinQ6ZWL3 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Co2+ MetaboliteCHEBI:27638 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
Cone apo-opsinsComplexR-HSA-2466081 (Reactome)
DHAMetaboliteCHEBI:36005 (ChEBI)
DHRS3ProteinO75911 (Uniprot-TrEMBL)
DHRS9 ProteinQ9BPW9 (Uniprot-TrEMBL)
FACYLsComplexR-ALL-2859065 (Reactome)
FAsComplexR-ALL-2864103 (Reactome)
FNTA(2-379) ProteinP49354 (Uniprot-TrEMBL)
FNTA:FNTBComplexR-HSA-2530496 (Reactome)
FNTB ProteinP49356 (Uniprot-TrEMBL)
FPPMetaboliteCHEBI:50277 (ChEBI)
GCAP1:Ca2+ComplexR-HSA-75339 (Reactome)
GCAP2:Ca2+ComplexR-HSA-75340 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GMPMetaboliteCHEBI:17345 (ChEBI)
GNAT1 (Met removed)ProteinP11488 (Uniprot-TrEMBL)
GNAT1-GDPComplexR-HSA-74062 (Reactome)
GNAT1-GTP:PDE6ComplexR-HSA-74056 (Reactome)
GNAT1-GTPComplexR-HSA-74049 (Reactome)
GNAT1ProteinP11488 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB1:GNGT1ComplexR-HSA-74061 (Reactome)
GNB5-1 ProteinO14775-1 (Uniprot-TrEMBL)
GNGT1ProteinP63211 (Uniprot-TrEMBL)
GRK1,4,7ComplexR-HSA-6787798 (Reactome)
GRK4-1 ProteinP32298-1 (Uniprot-TrEMBL)
GRK7 ProteinQ8WTQ7 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
GUCA1A ProteinP43080 (Uniprot-TrEMBL)
GUCA1AProteinP43080 (Uniprot-TrEMBL)
GUCA1B ProteinQ9UMX6 (Uniprot-TrEMBL)
GUCA1BProteinQ9UMX6 (Uniprot-TrEMBL)
GUCA1C ProteinO95843 (Uniprot-TrEMBL)
GUCA:Ca2+ComplexR-HSA-2586734 (Reactome)
GUCAComplexR-HSA-2586735 (Reactome)
GUCY2D ProteinQ02846 (Uniprot-TrEMBL)
GUCY2F ProteinP51841 (Uniprot-TrEMBL)
GUCYsComplexR-HSA-74883 (Reactome)
Gt-GDPComplexR-HSA-74063 (Reactome)
Gt-GTPComplexR-HSA-74064 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HSD17B1 ProteinP14061 (Uniprot-TrEMBL)
HSD17B6 ProteinO14756 (Uniprot-TrEMBL)
K+MetaboliteCHEBI:29103 (ChEBI)
L-MetMetaboliteCHEBI:57844 (ChEBI)
LINA MetaboliteCHEBI:17351 (ChEBI)
LINL MetaboliteCHEBI:32386 (ChEBI)
LRATProteinO95237 (Uniprot-TrEMBL)
METAP1 ProteinP53582 (Uniprot-TrEMBL)
METAP1/2ComplexR-HSA-2534069 (Reactome)
METAP2 ProteinP50579 (Uniprot-TrEMBL)
MYO7AProteinQ13402 (Uniprot-TrEMBL)
MYS-CoA MetaboliteCHEBI:15532 (ChEBI)
MYS-CoAMetaboliteCHEBI:15532 (ChEBI)
Me3K115-CALM1ProteinP0DP23 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
N-(C12:0)-GNAT1 ProteinP11488 (Uniprot-TrEMBL)
N-(C14:0)-GNAT1 ProteinP11488 (Uniprot-TrEMBL)
N-(C14:0)-GNAT1ProteinP11488 (Uniprot-TrEMBL)
N-(C14:1)-GNAT1 ProteinP11488 (Uniprot-TrEMBL)
N-(C14:2)-GNAT1 ProteinP11488 (Uniprot-TrEMBL)
N-acyl-GNAT1ComplexR-HSA-2534054 (Reactome)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NAPEPLDProteinQ6IQ20 (Uniprot-TrEMBL)
NMT1 ProteinP30419 (Uniprot-TrEMBL)
NMT1/2ComplexR-HSA-2649003 (Reactome)
NMT2 ProteinO60551 (Uniprot-TrEMBL)
NRPEMetaboliteCHEBI:71063 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OLEA MetaboliteCHEBI:16196 (ChEBI)
OLEL MetaboliteCHEBI:25667 (ChEBI)
OPN1LW ProteinP04000 (Uniprot-TrEMBL)
OPN1LWProteinP04000 (Uniprot-TrEMBL)
OPN1MW ProteinP04001 (Uniprot-TrEMBL)
OPN1MWProteinP04001 (Uniprot-TrEMBL)
OPN1SW ProteinP03999 (Uniprot-TrEMBL)
OPN1SWProteinP03999 (Uniprot-TrEMBL)
PAMetaboliteCHEBI:16337 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PALMMetaboliteCHEBI:15756 (ChEBI)
PALML MetaboliteCHEBI:45021 (ChEBI)
PDE6A(2-860) ProteinP16499 (Uniprot-TrEMBL)
PDE6B(1-851) ProteinP35913 (Uniprot-TrEMBL)
PDE6G ProteinP18545 (Uniprot-TrEMBL)
PDE6ComplexR-HSA-74055 (Reactome) cGMP selective hydrolase
PEMetaboliteCHEBI:16038 (ChEBI)
PPEF1 ProteinO14829 (Uniprot-TrEMBL)
PPEF1:Mg2+ComplexR-HSA-2632510 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCA/QComplexR-HSA-2648977 (Reactome)
PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
PhotonMetaboliteCHEBI:30212 (ChEBI)
PiMetaboliteCHEBI:43474 (ChEBI)
RBP1 ProteinP09455 (Uniprot-TrEMBL)
RBP1:atROLComplexR-HSA-2864101 (Reactome)
RBP1ProteinP09455 (Uniprot-TrEMBL)
RBP3ProteinP10745 (Uniprot-TrEMBL)
RBP4(19-201) ProteinP02753 (Uniprot-TrEMBL)
RCVRN ProteinP35243 (Uniprot-TrEMBL)
RCVRN:Ca2+ComplexR-HSA-3229219 (Reactome)
RDH10 ProteinQ8IZV5 (Uniprot-TrEMBL)
RDH10,11ComplexR-HSA-2454066 (Reactome)
RDH11 ProteinQ8TC12 (Uniprot-TrEMBL)
RDH12ProteinQ96NR8 (Uniprot-TrEMBL)
RDH16 ProteinO75452 (Uniprot-TrEMBL)
RDH5(1-318)-like ProteinsComplexR-HSA-4084692 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
RDH5(24-318) ProteinQ92781 (Uniprot-TrEMBL)
RDH8 ProteinQ9NYR8 (Uniprot-TrEMBL)
RDH8-like proteinsComplexR-HSA-4127419 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
REHR-HSA-2466001 (Reactome)
RGS9 isoform 3 ProteinO75916-3 (Uniprot-TrEMBL)
RGS9-1:GNB5:RGS9BPComplexR-HSA-74601 (Reactome)
RGS9BP ProteinQ6ZS82 (Uniprot-TrEMBL)
RHOProteinP08100 (Uniprot-TrEMBL)
RLBP1 ProteinP12271 (Uniprot-TrEMBL)
RLBP1:11cRALComplexR-HSA-2454060 (Reactome)
RLBP1:11cROLComplexR-HSA-2454078 (Reactome)
RLBP1:11cRPALMComplexR-HSA-8981408 (Reactome)
RLBP1:atROLComplexR-HSA-2465956 (Reactome)
RLBP1ProteinP12271 (Uniprot-TrEMBL)
RPE65ProteinQ16518 (Uniprot-TrEMBL)
Retinoid metabolism and transportPathwayR-HSA-975634 (Reactome) Vitamin A (all-trans-retinol) must be taken up, either as carotenes from plants, or as retinyl esters from animal food. The most prominent carotenes are alpha-carotene, lycopene, lutein, beta-cryptoxanthine, and especially beta-carotene. After uptake they are mostly broken down to retinal. Retinyl esters are hydrolysed like other fats. In enterocytes, retinoids bind to retinol-binding protein (RBP). Transport from enterocytes to the liver happens via chylomicrons (Harrison & Hussain 2001, Harrison 2005).
S-farn-GNGT1 ProteinP63211 (Uniprot-TrEMBL)
S-farn-GNGT1ProteinP63211 (Uniprot-TrEMBL)
S-farn-GRK1 ProteinQ15835 (Uniprot-TrEMBL)
S-farn-GRK1:RCVRN:Ca2+ComplexR-HSA-3229193 (Reactome)
S-farn-GRK1ProteinQ15835 (Uniprot-TrEMBL)
SAG ProteinP10523 (Uniprot-TrEMBL)
SAGProteinP10523 (Uniprot-TrEMBL)
SDR9C7 ProteinQ8NEX9 (Uniprot-TrEMBL)
SLC24A1ProteinO60721 (Uniprot-TrEMBL)
STEA MetaboliteCHEBI:9254 (ChEBI)
STEAL MetaboliteCHEBI:26753 (ChEBI)
STRA6 ProteinQ9BX79 (Uniprot-TrEMBL)
STRA6ProteinQ9BX79 (Uniprot-TrEMBL)
TTR ProteinP02766 (Uniprot-TrEMBL)
TTR:RBP4:STRA6ComplexR-HSA-2453860 (Reactome)
TTR:RBP4:atROL:STRA6ComplexR-HSA-2453850 (Reactome)
TTR:RBP4:atROLComplexR-HSA-2453705 (Reactome)
acyl-CoAComplexR-ALL-2534017 (Reactome)
at-retinyl-OPN1LW ProteinP04000 (Uniprot-TrEMBL)
at-retinyl-OPN1MW ProteinP04001 (Uniprot-TrEMBL)
at-retinyl-OPN1SW ProteinP03999 (Uniprot-TrEMBL)
at-retinyl-RHOProteinP08100 (Uniprot-TrEMBL)
at-retinyl-cone opsinsComplexR-HSA-2466087 (Reactome)
atR-LINA MetaboliteCHEBI:70762 (ChEBI)
atR-OLEA MetaboliteCHEBI:70760 (ChEBI)
atR-PALM MetaboliteCHEBI:17616 (ChEBI)
atR-STEA MetaboliteCHEBI:70761 (ChEBI)
atRALMetaboliteCHEBI:17898 (ChEBI)
atREsComplexR-ALL-2864099 (Reactome)
atROL MetaboliteCHEBI:17336 (ChEBI)
atROL isomeraseR-HSA-2465932 (Reactome)
atROLMetaboliteCHEBI:17336 (ChEBI)
cGMP MetaboliteCHEBI:16356 (ChEBI)
cGMP:CNG channelComplexR-HSA-74011 (Reactome)
cGMPMetaboliteCHEBI:16356 (ChEBI)
hydroxydocosahexaenoic acidMetaboliteCHEBI:72790 (ChEBI)
lauroyl-CoA MetaboliteCHEBI:15521 (ChEBI)
p-MII:SAGComplexR-HSA-2581511 (Reactome)
p-RHO:SAGComplexR-HSA-2632519 (Reactome)
p-S334,338,343-RHO ProteinP08100 (Uniprot-TrEMBL)
p-S334,338,343-RHOProteinP08100 (Uniprot-TrEMBL)
p-S334,338,343-at-retinyl-RHO ProteinP08100 (Uniprot-TrEMBL)
p-S334,338,343-at-retinyl-RHOProteinP08100 (Uniprot-TrEMBL)
p-S478-RGS9 isoform 3 ProteinO75916-3 (Uniprot-TrEMBL)
p-S478-RGS9-1:GNB5:RGS9BPComplexR-HSA-2648990 (Reactome)
unknown NATR-HSA-2565924 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
11c-retinyl-RHOArrowR-HSA-2454118 (Reactome)
11c-retinyl-RHOR-HSA-74101 (Reactome)
11c-retinyl-cone opsinsR-HSA-2465917 (Reactome)
11cRAL-OPN1LWArrowR-HSA-2465924 (Reactome)
11cRAL-OPN1MWArrowR-HSA-9656893 (Reactome)
11cRAL-OPN1SWArrowR-HSA-9656891 (Reactome)
11cRALArrowR-HSA-2454113 (Reactome)
11cRALArrowR-HSA-2465921 (Reactome)
11cRALArrowR-HSA-8960973 (Reactome)
11cRALR-HSA-2454113 (Reactome)
11cRALR-HSA-2454118 (Reactome)
11cRALR-HSA-2465924 (Reactome)
11cRALR-HSA-9656891 (Reactome)
11cRALR-HSA-9656893 (Reactome)
11cRDHmim-catalysisR-HSA-2465921 (Reactome)
11cROLArrowR-HSA-2453833 (Reactome)
11cROLArrowR-HSA-2465934 (Reactome)
11cROLArrowR-HSA-2465941 (Reactome)
11cROLR-HSA-2454264 (Reactome)
11cROLR-HSA-2465921 (Reactome)
11cROLR-HSA-2465934 (Reactome)
11cRPALMR-HSA-2465941 (Reactome)
A2EArrowR-HSA-2466831 (Reactome)
A2EArrowR-HSA-2467738 (Reactome)
A2EArrowR-HSA-2467761 (Reactome)
A2ER-HSA-2467738 (Reactome)
A2ER-HSA-2467761 (Reactome)
A2PEArrowR-HSA-2466764 (Reactome)
A2PER-HSA-2466831 (Reactome)
ABCA4mim-catalysisR-HSA-1467466 (Reactome)
ABCA4mim-catalysisR-HSA-2466749 (Reactome)
ADPArrowR-HSA-1467466 (Reactome)
ADPArrowR-HSA-2466749 (Reactome)
ADPArrowR-HSA-2581474 (Reactome)
ADPArrowR-HSA-74615 (Reactome)
ATPR-HSA-1467466 (Reactome)
ATPR-HSA-2466749 (Reactome)
ATPR-HSA-2581474 (Reactome)
ATPR-HSA-74615 (Reactome)
AWAT2mim-catalysisR-HSA-2465919 (Reactome)
AdoHcyArrowR-HSA-6786205 (Reactome)
AdoMetR-HSA-6786205 (Reactome)
CALM1:4xCa2+ArrowR-HSA-74448 (Reactome)
CALM1:4xCa2+R-HSA-3229181 (Reactome)
CALM1:Ca2+:CNG channelArrowR-HSA-3229181 (Reactome)
CALM1R-HSA-6786205 (Reactome)
CALM1R-HSA-74448 (Reactome)
CAMKMTmim-catalysisR-HSA-6786205 (Reactome)
CNG channelArrowR-HSA-2514865 (Reactome)
CNG channelR-HSA-3229181 (Reactome)
CNG channelR-HSA-74031 (Reactome)
CYP4V2mim-catalysisR-HSA-6786239 (Reactome)
Ca2+ArrowR-HSA-2514867 (Reactome)
Ca2+ArrowR-HSA-2514891 (Reactome)
Ca2+ArrowR-HSA-3229181 (Reactome)
Ca2+ArrowR-HSA-74948 (Reactome)
Ca2+R-HSA-2514867 (Reactome)
Ca2+R-HSA-2514891 (Reactome)
Ca2+R-HSA-2586748 (Reactome)
Ca2+R-HSA-74448 (Reactome)
Ca2+TBarR-HSA-2581474 (Reactome)
CoA-SHArrowR-HSA-2465919 (Reactome)
CoA-SHArrowR-HSA-2534040 (Reactome)
CoA-SHArrowR-HSA-2534087 (Reactome)
Cone apo-opsinsArrowR-HSA-2466085 (Reactome)
DHAR-HSA-6786239 (Reactome)
DHRS3mim-catalysisR-HSA-2465940 (Reactome)
FACYLsR-HSA-2453855 (Reactome)
FAsArrowR-HSA-2453833 (Reactome)
FNTA:FNTBmim-catalysisR-HSA-2530501 (Reactome)
FPPR-HSA-2530501 (Reactome)
GCAP1:Ca2+TBarR-HSA-74885 (Reactome)
GCAP2:Ca2+TBarR-HSA-74885 (Reactome)
GDPArrowR-HSA-2485180 (Reactome)
GMPArrowR-HSA-74059 (Reactome)
GNAT1 (Met removed)ArrowR-HSA-2534096 (Reactome)
GNAT1 (Met removed)R-HSA-2534040 (Reactome)
GNAT1 (Met removed)R-HSA-2534087 (Reactome)
GNAT1-GDPArrowR-HSA-2584246 (Reactome)
GNAT1-GDPR-HSA-74882 (Reactome)
GNAT1-GDPTBarR-HSA-74065 (Reactome)
GNAT1-GTP:PDE6ArrowR-HSA-74065 (Reactome)
GNAT1-GTP:PDE6R-HSA-2584246 (Reactome)
GNAT1-GTP:PDE6mim-catalysisR-HSA-2584246 (Reactome)
GNAT1-GTP:PDE6mim-catalysisR-HSA-74059 (Reactome)
GNAT1-GTPArrowR-HSA-2485182 (Reactome)
GNAT1-GTPR-HSA-74065 (Reactome)
GNAT1R-HSA-2534096 (Reactome)
GNB1:GNGT1ArrowR-HSA-2485182 (Reactome)
GNB1:GNGT1R-HSA-74882 (Reactome)
GNGT1R-HSA-2530501 (Reactome)
GRK1,4,7mim-catalysisR-HSA-2581474 (Reactome)
GTPR-HSA-2485180 (Reactome)
GTPR-HSA-74885 (Reactome)
GUCA1AArrowR-HSA-74885 (Reactome)
GUCA1BArrowR-HSA-74885 (Reactome)
GUCA:Ca2+ArrowR-HSA-2586748 (Reactome)
GUCA:Ca2+TBarR-HSA-74885 (Reactome)
GUCAR-HSA-2586748 (Reactome)
GUCYsmim-catalysisR-HSA-74885 (Reactome)
Gt-GDPArrowR-HSA-74882 (Reactome)
Gt-GDPR-HSA-2485180 (Reactome)
Gt-GTPArrowR-HSA-2485180 (Reactome)
Gt-GTPR-HSA-2485182 (Reactome)
H+ArrowR-HSA-2453833 (Reactome)
H+ArrowR-HSA-2454081 (Reactome)
H+ArrowR-HSA-2465921 (Reactome)
H+ArrowR-HSA-2465941 (Reactome)
H+ArrowR-HSA-74872 (Reactome)
H+R-HSA-2464803 (Reactome)
H+R-HSA-2464822 (Reactome)
H+R-HSA-2465940 (Reactome)
H+R-HSA-6786239 (Reactome)
H2OArrowR-HSA-2454118 (Reactome)
H2OArrowR-HSA-2465924 (Reactome)
H2OArrowR-HSA-2466764 (Reactome)
H2OArrowR-HSA-6786239 (Reactome)
H2OArrowR-HSA-9656891 (Reactome)
H2OArrowR-HSA-9656893 (Reactome)
H2OR-HSA-1467466 (Reactome)
H2OR-HSA-2453833 (Reactome)
H2OR-HSA-2465941 (Reactome)
H2OR-HSA-2466085 (Reactome)
H2OR-HSA-2466749 (Reactome)
H2OR-HSA-2466831 (Reactome)
H2OR-HSA-2584246 (Reactome)
H2OR-HSA-2632521 (Reactome)
H2OR-HSA-74059 (Reactome)
H2OR-HSA-74948 (Reactome)
K+ArrowR-HSA-2514891 (Reactome)
K+R-HSA-2514891 (Reactome)
L-MetArrowR-HSA-2534096 (Reactome)
LRATmim-catalysisR-HSA-2453855 (Reactome)
METAP1/2mim-catalysisR-HSA-2534096 (Reactome)
MYO7AArrowR-HSA-2453833 (Reactome)
MYS-CoAR-HSA-2534087 (Reactome)
Me3K115-CALM1ArrowR-HSA-6786205 (Reactome)
N-(C14:0)-GNAT1ArrowR-HSA-2534087 (Reactome)
N-acyl-GNAT1ArrowR-HSA-2534040 (Reactome)
NAD+R-HSA-2454081 (Reactome)
NADHArrowR-HSA-2454081 (Reactome)
NADP+ArrowR-HSA-2464803 (Reactome)
NADP+ArrowR-HSA-2464822 (Reactome)
NADP+ArrowR-HSA-2465940 (Reactome)
NADP+ArrowR-HSA-6786239 (Reactome)
NADP+R-HSA-2465921 (Reactome)
NADP+R-HSA-74872 (Reactome)
NADPHArrowR-HSA-2465921 (Reactome)
NADPHArrowR-HSA-74872 (Reactome)
NADPHR-HSA-2464803 (Reactome)
NADPHR-HSA-2464822 (Reactome)
NADPHR-HSA-2465940 (Reactome)
NADPHR-HSA-6786239 (Reactome)
NAPEPLDmim-catalysisR-HSA-2466831 (Reactome)
NMT1/2mim-catalysisR-HSA-2534087 (Reactome)
NRPEArrowR-HSA-2466749 (Reactome)
NRPEArrowR-HSA-2466846 (Reactome)
NRPER-HSA-2466718 (Reactome)
NRPER-HSA-2466749 (Reactome)
NRPER-HSA-2466764 (Reactome)
Na+ArrowR-HSA-2514867 (Reactome)
Na+ArrowR-HSA-2514891 (Reactome)
Na+R-HSA-2514867 (Reactome)
Na+R-HSA-2514891 (Reactome)
O2R-HSA-6786239 (Reactome)
OPN1LWR-HSA-2465924 (Reactome)
OPN1MWR-HSA-9656893 (Reactome)
OPN1SWR-HSA-9656891 (Reactome)
PAArrowR-HSA-2466831 (Reactome)
PALM-CoAR-HSA-2465919 (Reactome)
PALMArrowR-HSA-2465941 (Reactome)
PDE6ArrowR-HSA-2584246 (Reactome)
PDE6R-HSA-74065 (Reactome)
PEArrowR-HSA-2466718 (Reactome)
PER-HSA-2466846 (Reactome)
PPEF1:Mg2+mim-catalysisR-HSA-74948 (Reactome)
PPiArrowR-HSA-2530501 (Reactome)
PPiArrowR-HSA-74885 (Reactome)
PRKCA/Qmim-catalysisR-HSA-74615 (Reactome)
PhotonR-HSA-2465917 (Reactome)
PhotonR-HSA-74101 (Reactome)
PiArrowR-HSA-1467466 (Reactome)
PiArrowR-HSA-2466749 (Reactome)
PiArrowR-HSA-2584246 (Reactome)
PiArrowR-HSA-74948 (Reactome)
R-HSA-1467466 (Reactome) Rhodopsin (RHO) is localised to both the disc membrane and the plasma membrane of rod outer segments (ROS). All-trans-retinal (atRAL) released from rhodopsin during the bleaching process, needs to translocate to the cytosol for reduction to all-trans-retinol (atROL) via all-trans-retinol dehydrogenases. Although atRAL can diffuse through membranes unaided, there exists an ABC transporter on disc membranes which may facilitate the transport of excess atRAL. Retinal-specific ATP-binding cassette transporter (ABCA4, ABCR) is the only ABC transporter which mediates the transport of retinoids (Biswas & Biswas 2000). Studies using bovine ABCA4 demonstrates atRAL transport (Sun et al. 1999). Human ABCR was found to be identical to the ABC transporter linked to Stargardt's disease type 1 (STGD1, MIM:248200), a cause of macular degeneration in childhood (Nasonkin et al. 1998).
R-HSA-2453833 (Reactome) All-trans-retinol esters (atREs) serve as substrates for retinoid isomerohydrolase (RPE65), located in retinal pigment epithelium (RPE) cells. RPE65 hydrolyses atREs to 11-cis-retinol (11cROL), thus performing an isomerase activity as well as hydrolysis. RPE65 is membrane-bound, this being dependent on the palmitylation of the residue Cys-112 (Takahashi et al. 2009). RPE65 normally undergoes a light-dependent translocation to become more concentrated in the central region of RPE cells. This translocation requires Unconventional myosin-VIIa (MYO7A or USH1B) (Lopes et al. 2011).
R-HSA-2453855 (Reactome) Lecithin retinol acyltransferase (LRAT) mediates the esterification of all-trans-retinol (atROL) to form all-trans-retinyl esters (atREs). atREs are stored in lipid droplet form called retinosomes (Imanishi et al. 2004). Cellular retinol-binding protein 1 (RBP1) is an effective donor of atROL for LRAT (Ruiz et al. 1999). LRAT is an important enzyme required for the clearance of atROL as it drives the uptake of atROL from the bloodstream through the receptor STRA6 (Kawaguchi et al. 2011) and clearance of atROL from rod outer segments (ROS). In addition, the esterified form of atROL serves as substrate for RPE65.
R-HSA-2453863 (Reactome) Stimulated by retinoic acid gene 6 protein homologue (STRA6) acts as a high-affinity cell-surface receptor for the TTR:RBP4:atROL complex (Berry et al. 2012). Once bound, STRA6 removes atROL and transports it into cells expressing STRA6 receptors, including eye (Kawaguchi et al. 2007). Defects in STRA6 cause microphthalmia syndromic type 9 (MCOPS9, Matthew-Wood syndrome or Spear syndrome; MIM:601186) (Chassaing et al. 2009). The uptake of atROL is driven by the conversion of atROL to retinyl ester (RE) by LRAT (Kawaguchi et al. 2011).
R-HSA-2453876 (Reactome) All-trans-retinol (atROL) circulates in the bloodstream in complex with transthyretin (TTR) and retinol- binding protein 4 (RBP4). The receptor Stimulated by retinoic acid gene 6 protein homologue (STRA6) acts as a high-affinity cell-surface receptor for the complex (Berry et al. 2012), removing atROL and transporting it into tissues expressing STRA6, including the eyes (Kawaguchi et al. 2007).
R-HSA-2454081 (Reactome) Another member of the short-chain dehydrogenases/reductases (SDR) family, RDH5, can (reversibly) catalyse the oxidation of 11-cis-retinol (11cROL) to 11-cis-retinal (11cRAL) in retinal pigment epithelium (RPE) cells using NAD+ as cofactor (Simon et al. 1996, Gonzalez-Fernandez et al. 1999). Cellular retinaldehyde-binding protein (RLBP1), the protein bound to 11cRAL in RPE, is not present in photoreceptor cells.
R-HSA-2454113 (Reactome) Interphotoreceptor retinoid-binding protein (RBP3) is the major soluble protein in the interphotoreceptor matrix (IPM) (Liou et al. 1989, Fong & Bridges 1988). It is thought to shuttle 11-cis-retinal (11cRAL) between retinal pigment epithelium (RPE) and photoreceptor outer segments during the visual cycle but the mechanism is poorly understood (Gonzalez-Fernandez & Ghosh 2008).
R-HSA-2454118 (Reactome) Human opsin-2 is a G-protein coupled photoreceptor found in the disc membranes of rod outer segments (ROS) (Nathans & Hogness 1984). It is an integral membrane protein and covalently binds the chromophore 11-cis-retinal (11cRAL) to form rhodopsin (RHO). Binding occurs via a protonated Schiff base linkage at Lys-296 (Fan et al. 2002) with Glu-113 at helix 3 serving as the counterion of the protonated Schiff base (Han et al. 1993). The resultant 11-cis-retinyl (11c-retinyl) group attached to lysine is completely embedded within the RHO structure. Opsins found in cone outer segments which bind 11cRAL are described in the cone visual cycle. Unlike other GPCRs in which direct ligand binding activates the receptor, rhodopsin is in an inactive state when bound to 11c-retinyl (which acts as an inverse agonist).
R-HSA-2454264 (Reactome) Cellular retinaldehyde-binding protein (RLBP1, CRALBP) (Intres et al. 1994) is abundant in retinal pigment epithelium (RPE) and Muller cells of the retina where it plays a role in sequestering 11-cis retinoids produced during the retinoid cycle. The natural ligands are 11-cis-retinol (11cROL) and 11-cis-retinal (11cRAL) (Crabb et al. 1998).
R-HSA-2464803 (Reactome) The reversible, NADP(H)-dependent reduction of all-trans-retinal (atRAL) to all-trans-retinol (atROL) occurs in both rod and cone photoreceptor cells where multiple retinol dehydrogenases (RHDs) are located. RHDs belong to the short-chain dehydrogenase/reductase (SDR) superfamily. RDH8 (located in photoreceptor outer segments) is partially responsible, together with other RDHs, for mediating this reaction. The activity for human RDH8 is inferred from a bovine experiment (Rattner et al. 2000).
R-HSA-2464809 (Reactome) Although interphotoreceptor retinoid-binding protein (RBP3, IRBP) (Fong & Bridges 1988, Fong et al. 1990) is not required to move all-trans-retinol (atROL) from photoreceptor cells to the retinal pigment epithelium (RPE), it may function to regulate retinoid trafficking and possibly protect retinoids from biochemical damage. RBP3 is secreted by photoreceptor cells into the interphotoreceptor matrix (IPM), where, being a larger protein (135kDa) than the IPM space, becomes trapped (see mini-review Gonzalez-Fernandez & Ghosh 2008). It is through this space that retinoids move between the RPE and photoreceptor outer segments during the retinoid cycle. Once atROL enters the RPE, it binds with RBP1.
R-HSA-2464810 (Reactome) The majority of all-trans-retinal (atRAL) simply diffuses across membranes into the cytosol. Experiments performed with mice rods demonstrate that atRAL diffusion is independent of assisted transport by ABCA4 (Mata et al. 2000, Blakeley et al. 2011).
R-HSA-2464822 (Reactome) The reversible, NADP(H)-dependent reduction of all-trans-retinal (atRAL) to all-trans-retinol (atROL) occurs in both rod and cone photoreceptor cells where multiple retinol dehydrogenases (RHDs) are located. RHDs belong to the short-chain dehydrogenase/reductase (SDR) superfamily. RDH12 (located in photoreceptor inner segments) is partially responsible, together with other RDHs, for mediating this reaction (Belyaeva et al. 2005).
R-HSA-2465917 (Reactome) Upon photon absorption, 11-cis-retinal (11cRAL) is isomerised to all-trans-retinal (atRAL). The structure of cone opsins which can ultimately activate G-proteins to initiate phototransduction is denoted as R* (Fan et al. 2002). R* is still bound to atRAL at this stage. The isomerisation is a very fast photochemical process (femtoseconds) (Schoenlein et al. 1991) followed by slower events described in the following reaction.
R-HSA-2465919 (Reactome) The esterification of alcohols with fatty acids is the favoured mechanism to form esterified forms of sterols, di- and triacylglycerols, and retinoids for storage. In the RPE and Muller cells of the eye, formation of retinyl esters is an essential step in the enzymatic regeneration of the visual chromophore 11-cis-retinal (11cRAL). Acyl-CoA wax alcohol acyltransferase 2 (AWAT2, aka Multifunctional O-acyltransferase, MFAT) (Yen et al. 2005) is an ER-membrane protein with a broad substrate specificity that can also esterify 11-cis retinol (11cROL) (Kaylor et al. 2014). The most common fatty acid is palmitate, forming retinyl palmitate (11cRPALM). Retinyl esters form into lipid droplets called retinosomes. In the previous step, retinol isomerase activity produces a mixture of retinol isomers (9-cis, 11-cis, 13-cis and all-trans-retinol) of which 11cROL only constitutes around 1% of the mixture. AWAT2’s preferential activity towards 11cROL has been proposed to be due to an allosteric modulation of AWAT2 by either bound (to RLBP1) or free 11cis-retinyl esters such as 11cRPALM. 11cRPALM impedes the acyl transfer onto 9-cis, 13-cis and all-trans retinols by making allosterically-induced changes in the active site of AWAT2 (Arne et al. 2017).
R-HSA-2465921 (Reactome) 11-cis-specific retinol dehydrogenase (11cRDH) activity found in chicken retina mediates the oxidation of 11-cis-retinol (11cROL) to 11-cis-retinal (11cRAL) using NADP+ as cofactor (Mata et al. 2002). The chicken protein that possesses this activity has not yet been identified. The actual enzyme responsible remains to be identified in human, even as evidence exists for this activity and for the alternative retinoid (visual) cycle in cones (Wang & Kefalov 2009). 11cRAL is the visual chromophore that is able to bind to opsins.
R-HSA-2465924 (Reactome) Human apo opsin proteins covalently bind the chromophore 11-cis-retinal (11cRAL) via a Schiff base linkage to a lysine residue in the seventh transmembrane alpha helix that is conserved in all known opsins (see review Shichida & Matsuyama 2009). The Schiff base linkage effectively results in an 11-cis-retinyl (11c-retinyl) group covalently linking to a lysine residue of opsins with subsequent loss of water. The three human cone opsins are Long Wavelength Sensitive Opsin (OPN1LW), Short Wavelength Sensitive Opsin (OPN1SW) and Middle Wavelength Sensitive Opsin (OPN1MW), sensing red, blue and green regions of the light spectrum, respectively (Nathans et al. 1986, Nathans et al. 1986b, Oprian et al. 1991).
R-HSA-2465926 (Reactome) The canonical rod retinoid (visual) cycle is too slow to account for the photosensitivity of cones in bright light conditions. Novel enzyme activities demonstrated in ground-squirrel and chicken retinas produce a novel pathway of chromophore regeneration specific for cones. The first reaction in Muller cells, the isomerization of all-trans-retinol (atROL) to 11-cis-retinol (11cROL), is mediated by an as-yet-uncharacterised atROL isomerase (Mata et al. 2002, Mata et al. 2005). This reaction is proposed to take place in all vertebrates including humans (Wang & Kefalov 2009). Sphingolipid delta(4)-desaturase DES1 (DEGS1), an enzyme involved in sphingolipid de-novo biosynthesis, was recently found to possess retinoid isomerisation activity in chicken retinas but its physiological relevance in the synthesis of 11cROL remains inconclusive (Kaylor et al. 2013, Kiser et al. 2014).
R-HSA-2465934 (Reactome) The transfer of 11-cis-retinol (11cROL) from Muller cells to cone photoreceptor cells is thought to be mediated by interphotoreceptor retinoid-binding protein RBP3 (Liou et al. 1989, Fong & Bridges 1988) but the mechanism is poorly understood (Gonzalez-Fernandez & Ghosh 2008).
R-HSA-2465938 (Reactome) All-trans-retinol (atROL), the product of the reduction of all-trans-retinal (atRAL) released from rod and cone opsins, needs to be regenerated back to the visual chromophore 11-cis-retinal (11cRAL). For the regenerative steps, rods transports atROL back into the retinal pigment epithelium (RPE) while cones utilise Muller cells. Although interphotoreceptor retinoid-binding protein (RBP3, IRBP) (Fong & Bridges 1988, Fong et al. 1990) is not thought to be required to move all-trans-retinol (atROL) from photoreceptor cells to the retinal pigment epithelium (RPE) or Muller cells, it may function to regulate retinoid trafficking and possibly protect retinoids from biochemical damage. RBP3 is secreted by photoreceptor cells into the interphotoreceptor matrix (IPM), where, being a larger protein (135kDa) than the IPM space, becomes trapped (see mini-review Gonzalez-Fernandez & Ghosh 2008). It is through this space that retinoids move between Muller cells and cone photoreceptor outer segments during the cone retinoid cycle.
R-HSA-2465940 (Reactome) All-trans-retinal (atRAL) can diffuse across membranes to the cytosol and is reduced to all-trans-retinol (atROL) by the action of a short-chain dehydrogenase/reductase 3 using NADP+/NADPH as cofactor (Haeseleer et al. 1998).
R-HSA-2465941 (Reactome) This human event has been inferred from an as-yet-uncharacterised protein which has been demonstrated to possess retinyl ester hydrolase (REH) activity in chicken retina to hydrolyse 11-cis-retinyl palmitate (11cRPALM) to 11-cis-retinol (11cROL) (Bustamante et al. 1995).
R-HSA-2465971 (Reactome) Retinaldehyde-binding protein 1 (RLBP1, also called cellular retinaldehyde-binding protein, CRALBP) (Crabb et al. 1998) binds 11cROL (He et al. 2009) and is thought to enhance the activity of isomerase II and ARAT in experiments performed in cone-rich eyes from chickens (Mata et al. 2002, Mata et al. 2005).
R-HSA-2466085 (Reactome) After the very fast isomerisation of the 11-cis-retinyl (11c-retinyl) group to the all-trans-retinyl (at-retinyl) group attached to opsins by light stimulation, slower events lead to exposure of at-retinyl group to the aqueous environment, resulting in the hydrolysis of the Schiff base linkage. Although other intermediate products are formed, the ultimate result is the release of all-trans-retinal (atRAL) from opsins, with apo-opsins being reformed (Baumann & Bender 1973). These series of slow decay reactions are called light bleaching of opsin and ends when atRAL, which can diffuse across membranes to the cytosol, is reduced to all-trans-retinol (atROL)
R-HSA-2466718 (Reactome) Once NRPE is "flipped" to the cytoplasmic side of disc membranes by the ABC transporter ABCA4, it can dissociate to all-trans-retinal (atRAL) and phosphatidylethanolamine (PE). atRAL is thus released to re-enter the retinoid cycle to reform the visual chromophore 11-cis-retinal (11cRAL) (Tsybovsky et al. 2010).
R-HSA-2466749 (Reactome) Bovine studies (Beharry et al. 2004) have indicated NRPE to be the preferred substrate for ABCA4 (ABCR, rim protein, RmP) (Azarian et al. 1998), which acts as an inward-directed retinoid flippase and facilitates the transfer of NRPE to the cytoplasmic side of the disc membrane. This transfer is essential to avoid build up of potentially toxic retinoid intermediates which are implicated in many retinal degenerative diseases (see review Tsybovsky et al. 2010). Defective ABCA4 cannot perform this function leading to impaired vision and blindness disorders such as Stargardt disease (MIM:248200).
R-HSA-2466764 (Reactome) A phosphatidyl-pyridinium bisretinoid compound, A2PE, is formed through condensation of N-retinylidene-PE (NRPE) and a second all-trans-retinol (atRAL) molecule (Parish et al. 1998, Mata et al. 2000). This most likely happens when atRAL is abundant.
R-HSA-2466831 (Reactome) The outer segment of photoreceptor cells is shed every 10-14 days to be completely replaced. The shed material is phagocytosed and transferred to the retinal pigment epithelium (RPE). Diretinoid-pyridinium-phosphatidylethanolamine (A2PE) can be hydrolysed to diretinoid-pyridinium-ethanolamine (A2E), a prominent constituent of lipofuscin (the material deposited in retinal tissue which accumulates over time and is implicated in macular degeneration). Evidence suggests this happens before transfer to RPE cells as part of the phagocytosed outer segment. A2E has been detected in outer segments (Ben-Shabat et al. 2002) and an N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD) activity detected in rat, mouse and human proteins (Okamoto et al. 2004, Ueda et al. 2005, Wang et al. 2006). This activity has been shown to hydrolyse A2PE to A2E in bovine outer segments before phagocytosis and transfer to RPE cells, suggesting A2PE is hydrolysed to A2E in photoreceptor outer segment membranes (Sparrow et al. 2003, Salvador & Giusto 1998).
R-HSA-2466846 (Reactome) In the disc membranes of photoreceptor outer segments, all-trans-retinal (atRAL) can spontaneously and reversibly react with phosphatidiylethanolamine (PE, cephalin; a phospholipid found in in membranes) to form a Schiff base product, N-retinylidene-phosphatidylethanolamine (NRPE) (Poincelot et al. 1969, Parish et al. 1998, Mata et al. 2000). Then, either NRPE is "flipped" over to the cytoplasmic side of disc membranes by ABCA4 where it can dissociate (thus releasing atRAL to re-enter the retinoid cycle) or it can condense with another atRAL to form a toxic diretinal compound. The route taken is determined by whether a functional ABCA4 protein is present or not.
R-HSA-2467738 (Reactome) Once photoreceptor outer segments are phagocytosed, inclusive of A2E, they are delivered to retinal pigment epithelial (RPE) cells for disposal. However, A2E has been shown to be resistant to any sort of degradative enzyme thus accumulates in the RPE. The relationship between lipofuscin accumulation and retinal degeneration is illustrated by Stargardt disease type 1 (STGD1, MIM:248200) (Allikmets et al. 1997).
R-HSA-2467761 (Reactome) Early experiments in frog and other species determined that the outer segments of photoreceptors are renewed by phagocytosis and transfer to retinal pigment eplithelial (RPE) cells for processing. A2E, formed in disc membranes of outer segments, is taken along with the phagolysosome (Young 1967, Young & Bok 1969, Katz et al. 1986). Here, for simplicity, only A2E is shown in the phagolysosome.
R-HSA-2485180 (Reactome) In darkness, the G protein transducin (Gt) is attached to the disk membrane surface with a GDP bound to it and it is inactive. Gt is a heterotrimer of alpha1 (GNAT1) (van Dop et al. 1989, Fong 1992), beta1 (GNB1) (Codina et al. 1986) and gamma1 (GNGT1) (Tao et al. 1993) subunits. Photoactivated rhodopsin (MII or R*) catalyzes the exchange of GTP for GDP bound to Gt. Upon GTP/GDP exchange, Gt is released from MII and the Gt alpha with GTP bound (GNAT1 GTP) dissociates from Gt beta gamma subunits (GNB1:GNGT1). This mechanism was deciphered from bovine experiments (Pugh & Lamb 1993). MII proceeds to activate additional Gt molecules, making this reaction the first amplification step in the phototransduction cascade. A single activated rhodopsin molecule activates tens of Gt molecules. Although phosphorylation of activated rhodopsin (MII) by rhodopsin kinase (GRK1) reduces transducin activation (Khani et al. 1996), complete deactivation occurs only after arrestin (S-antigen or SAG, Yamaki et al. 1988) binds to and sterically caps MII.

Defects in GNAT1 cause the Nougaret type of autosomal dominant, congenital stationary night blindness (Dryja et al. 1996, CSNBAD3; MIM:610444) . Congenital stationary night blindness is a non progressive retinal disorder characterized by impaired night vision.
R-HSA-2485182 (Reactome) Binding of transducin (Gt) to activated rhodopsin (MII) promotes the release of GDP from the Gt alpha subunit enabling a GTP (present in a higher concentration than GDP) to take its place. With GTP bound, Gt alpha (GNAT1-GTP) dissociates from the Gt beta:gamma subunits (GNB1:GNGT1) and from MII. MII is then available to bind and activate additional transducins. Transducin activation is the first amplifying step in visual transduction. Many findings came from bovine experiments (Pugh & Lamb 1993, Fung & Stryer 1980, Fung et al. 1981, Hofmann 1985).
R-HSA-2514865 (Reactome) As cGMP is hydrolysed during the activation phase of phototransduction, its intracellular concentration decreases leading to the closure of CNG channel (the closed status is designated as CNG channel) (Dhallan et al. 1992, Chen et al. 1993). Channel closure reduces the inward flux of sodium and calcium (also known as the 'dark current') resulting in cell hyperpolarisation. Cooperative binding of cGMP to the CNG channel confers additional amplification to the phototransduction cascade (Pugh & Lamb 1993, Yau & Baylor 1989).
R-HSA-2514867 (Reactome) The cGMP-gated (CNG) channels are heterotetramers of three alpha subunits (CNGA1) and one beta subunit (CNGB1). Although the subunits bear structural similarities to voltage-gated potassium channels, the rod channel is only weakly voltage sensitive (Chen et al. 1993). Opening occurs with cGMP bound and rarely occurs in the absence of cGMP (hence the closed state is designated as CNG channel and the open status is designated as cGMP:CNG channel). In darkness, cGMP concentration is relatively high and cGMP-gated cation (CNG) channels are open to allow the influx of cations into the rod outer segment. The inward current is composed mainly of Na+ ions, with lesser contributions from Ca2+ ions and Mg2+ ions (Dhallan et al. 1992). The channel is outwardly rectifying so that over physiological membrane potentials, the inward current is proportional to the number of channels open and is nearly independent of voltage. Mutations in the CNG channel subunits can cause a recessive form of retinitis pigmentosa (https://sph.uth.edu/retnet/).
R-HSA-2514891 (Reactome) Intracellular Ca2+ is extruded from the outer segment by a Na+/Ca2+, K+ exchanger (NCKX1 encoded by SLC24A1) (Tucker et al. 1998). Operation of the exchanger is electrogenic; 4 Na+ enter and 1 K+ exits for every Ca2+ removed for a net movement of 1 positive charge inward per duty cycle. In bright light, when all of the CNG channels are closed, the exchanger continues to remove Ca2+, reducing intracellular Ca2+ by an order of magnitude. Mutations in SLC24A1 can give rise to recessive congenital stationary night blindness (Riazuddin et al. 2010).
R-HSA-2530501 (Reactome) Prenylation is the process of post-translational addition of hydrophobic groups to proteins and is thought to help anchor proteins to cellular membranes. Farnesylation is a type of prenylation, where a farnesyl group (donated from farnesyl diphosphate, FPP) is added to a cysteine residue on a protein. The enzyme mediating this transfer is farnesyltransferase (FNT). FNT is a heterodimer comprising an alpha subunit (common to another prenylating enzyme called geranylgeranyltransferase, GGT) and a unique beta subunit (Long et al. 2001, Bell et al. 2002, deSolms et al. 2003). This complex recognises the CAAX box (C is the cysteine, A is any aliphatic amino acid, and X determines which enzyme acts on the protein) at the C-terminus of the target protein, in this case, the gamma subunit of transducin (GNG1) (Omer at al. 1993).
R-HSA-2534040 (Reactome) After removal of the N-terminal methionine (Met) residue, an unknown N-acyltransferase, similar to the enzymes glycylpeptide N-tetradecanoyltransferase 1 and 2 (NMT1 and 2), mediates the transfer of acyl groups from acyl-CoA to the now N-terminal glycine (Gly) residue of transducin's alpha subunit (GNAT1). The fatty acyl groups transferred are lauroyl (C12:0) and unsaturated myristoyl groups (C14:2 and C14:1). Myristoylation is thought to aid enzyme function and localization. This human event is inferred from bovine experiments demonstrating this activity (Kokame et al 1992).
R-HSA-2534087 (Reactome) After removal of the N-terminal methionine (Met) residue, the enzymes glycylpeptide N-tetradecanoyltransferase 1 and 2 (NMT1 and 2) mediate the transfer of the myristoyl (MYS) group from myristoyl-CoA to the now N-terminal glycine (Gly) residue of transducin's alpha subunit (GNAT1) (Glover et al. 1997, Giang & Cravatt 1998). Myristoylation is thought to aid enzyme function and localization. Evidence from chicken experiments suggest non-myristoylated proteins do not bind to membranes (Kamps et al. 1986).
R-HSA-2534096 (Reactome) All eukaryotic proteins synthesized in the cytosol are initiated by methionine (Met). For the maturation of many proteins, the removal of N-terminal Met is essential and is mediated by methionine-aminopeptidases (METAPs). In human, there are two forms, METAP1 and 2 (Arfin et al. 1995). These enzymes utilise 2 cobalt ions (Co2+) as cofactors (Addlagatta et al. 2005, Hu et al. 2006, Marino et al. 2007).
R-HSA-2581474 (Reactome) Activated rhodopsin (MII aka R*) must be deactivated to terminate the single photon response. Deactivation begins during the rising phase of the single photon response after MII binds rhodopsin kinase (GRK1), a serine/threonine protein kinase (Khani et al. 1996). GRK1 is activated by MII whereupon it phosphorylates MII at multiple serine and threonine sites on its C terminus. There are six serine and threonine residues that can be phosphorylated. Increasing phosphorylation progressively reduces the rate at which MII can activate transducin but full quenching requires the binding of arrestin (S-antigen or SAG, Yamaki et al. 1988) which binds to and sterically caps MII (Burns & Pugh 2010, Korenbrot 2012). GRK4-alpha (isoform 1) and GRK7 are also able to phosphorylate rhodopsin thereby deactivating it (Premont et al. 1996, Chen et al. 2001, Horner et al. 2005, Osawa et al. 2008).

A substantial fraction of rhodopsin kinase (GRK1) is bound to recoverin (RCVRN) in darkness, when internal Ca2+ levels are high. RCVRN is an EF-hand protein (Murakami et al. 1992) that functions as a myristoyl switch. With Ca2+ bound, the myristoyl group is exposed to attach RCVRN to the membrane. When Ca2+ levels drop with light exposure, Ca2+ dissociates from RCVRN and GRK1 is released. Higher levels of free GRK1 accelerate the phosphorylation and shutoff of photoexcited rhodopsin (MII).

Certain mutations in GRK1 cause Oguchi type 2 disease, a rare, recessive form of congenital stationary night blindness (https://sph.uth.edu/retnet/).
R-HSA-2581488 (Reactome) Although phosphorylation of activated rhodopsin (MII) reduces transducin activation, complete deactivation occurs only after arrestin (S-antigen or SAG, Yamaki et al. 1988) binds to and sterically caps MII. SAG is capable of binding unphosphorylated MII, but with very low probability. Binding affinity increases greatly upon phosphorylation. Binding of SAG generally occurs after MII has been phosphorylated ~3 times, and binding prevents further phosphorylation. Interestingly, rods express a small amount of a splice variant of SAG, P44, but its function is not yet known. Defects in SAG cause Oguchi type 1 disease (CSNBO1; MIM:258100), a recessive form of congenital stationary night blindness characterized by impaired scotopic vision (Fuchs et al. 1995).
R-HSA-2584246 (Reactome) Active Gt alpha (GNAT-GTP) can be inactivated by a slow, intrinsic GTPase activity that hydrolyses GTP to GDP. Once GNAT1 has GDP bound, it no longer binds to the gamma subunit of PDE6 (PDE6-gamma) that then resumes inhibition of the catalytic subunit of PDE6. The hydrolysis of GTP is accelerated by a GAP (GTPase accelerating protein) complex that consists of Regulator of G protein signaling 9 (RGS9-1, RGS9 isoform 3) (He et al. 1998, Zhang et al. 1999), Guanine nucleotide binding protein subunit beta 5, long form (GNB5) (Makino et al. 1999) and RGS9 anchoring protein (RGS9BP, aka R9AP) (Hu & Wensel 1998). The affinity of GNAT GTP for the GAP complex is relatively low, but is increased significantly by the presence of PDE-gamma. Shutoff of Gt is the rate-limiting step in the recovery of the single photon response of rods (Chen et al. 2000, Krispel et al. 2006). Persons with defective GAP experience bradyopsia or "slow vision" in which there are difficulties in adjusting to changes in brightness and to tracking moving objects (Michaelides et al. 2010, Nishiguchi et al. 2004).
R-HSA-2586748 (Reactome) The activity of guanylyl cyclases is regulated by Ca2+-binding, guanylyl cyclase-activating proteins (GCAPs). This regulation is the most important negative feedback mechanism triggered by Ca2+ in light. There are three GCAPs in humans; GUCA1A (Subbaraya et al. 1994), GUCA1B (Surguchov et al. 1997) and GUCA1C (Haeseleer et al. 1999). In darkness, when intracellular Ca2+ is relatively high, GCAPs suppress guanylate cyclase activity. But the light-induced fall in Ca2+ prompts Ca2+ to dissociate from GCAPs and be replaced by Mg2+, allowing the GCAPs to stimulate guanylate cyclase activity by an order of magnitude. Different GCAPs have different affinities for Ca2+. Defects in GCAP1 give rise to cone dystrophy and Lebers congenital amaurosis (https://sph.uth.edu/retnet/).

R-HSA-2632521 (Reactome) Eventually the Schiff base linkage between the all-trans-retinyl (at-retinyl) group and opsin is hydrolyzed, releasing all-trans-retinal (atRAL). atRAL repositions to an "exit" site within opsin and is reduced to all-trans-retinol (atROL) by retinol dehydrogenases RDH8 and RDH12 using NADPH as cofactor (see section on rod retinoid cycle), whereupon it exits the rod (Baumann & Bender 1973).
R-HSA-3229181 (Reactome) As the channels reopen, rising Ca2+ levels result in binding of Ca2+ to calmodulin (CALM1). By targeting the beta subunit of the channel, CALM1:Ca2+ reduces the apparent affinity of the channel for cGMP (Chen et al. 1994, Hsu & Molday 1993, Hsu & Molday 1994).
R-HSA-3229213 (Reactome) A substantial fraction of rhodopsin kinase (GRK1) is bound to recoverin (RCVRN) in darkness, when internal Ca2+ levels are high. RCVRN is an EF-hand protein (Murakami et al. 1992) that functions as a myristoyl switch. With Ca2+ bound, the myristoyl group is exposed to attach RCVRN to the membrane. When Ca2+ levels drop with light exposure, Ca2+ dissociates from RCVRN and GRK1 is released. Higher levels of free GRK1 accelerate the phosphorylation and shutoff of photoexcited rhodopsin (MII). However, this feedback mechanism proceeds too slowly to impact the single photon response that was responsible for causing the fall in Ca2+. Instead, it operates during light adaptation, where the light-induced fall in Ca2+ primes the rod to release GRK1 to act after subsequent photoisomerizations of rhodopsin. RCVRN also serves as a Ca2+ buffer within the rod outer segment. Although mutations in RCVRN are not known to cause retinal disease, some cancer-associated retinopathies result from an autoimmune attack on RCVRN (Polans et al. 1991).
R-HSA-6786205 (Reactome) Calmodulin (CALM1) is a ubiquitous key mediator of Ca2+-dependent signalling and is subject to regulatory post-translational modifications which can affect protein-protein interactions. CALM1 is frequently trimethylated at Lys-115 which can influence changes in growth and development and its activator properties with target enzymes. The cytosolic enzyme calmodulin-lysine N-methyltransferase (CAMKMT) catalyses the transfer of 3 methyl groups from high energy donors S-adenosyl-L-methionine (AdoMet) to lysine residue 115 in CALM1, forming a trimethylated protein (triMe-K115-CALM1) (Magnani et al. 2010).
R-HSA-6786239 (Reactome) The main physiological function of normal retinal photoreceptor epithelial (RPE) cells is to import polyunsaturated fatty acids (PUFAs) from the bloodstream and to recycle them to maintain lipid homeostasis in photoreceptors. CYP4 enzymes are microsomal fatty acid omega-hydroxylases that function to degrade cellular lipids. CYP4V2 is present in epithelial cells of the retina and cornea, localised to the endoplasmic reticulum membrane and can hydroxylate PUFAs to their respective omega-hydroxylated products. Docosahexaenoic acid (DHA), which is found at high concentrations in the eye, is a C22 PUFA which is hydroxylated to omega-hydroxy-DHA (Nakano et al. 2009, 2012). Defects in CYP4V2 can cause Bietti crystalline corneoretinal dystrophy (BCD; MIM:210370), an ocular disease characterised by retinal degeneration and marginal corneal dystrophy resulting in progressive night blindness and constriction of the visual field. A typical feature is multiple glistening intraretinal crystals scattered over the fundus (Li et al. 2004, Nakano et al. 2012).
R-HSA-74031 (Reactome) Once cGMP concentration is restored to "dark" levels, it binds cooperatively to the cGMP-gated cation channel (CNG channel), inducing opening through a conformational change in the channel (open status designated as cGMP:CNG channel here) (Chen et al 1993, Dhallan et al. 1992).
R-HSA-74059 (Reactome) Phosphodiesterase 6 (PDE6, Pittler et al. 1990, Tuteja et al. 1990, Weber et al. 1991) undergoes brief, spontaneous activations every few minutes to sustain a low, basal rate of 3',5' cyclic GMP (cGMP) hydrolysis to 5’ GMP (Cobbs 1991, Dawis et al. 1988, Hodgkin & Nunn 1988, Rieke & Baylor 1996, Wensel & Stryer 1986). However, activated transducin (GNAT1-GTP) sustains PDE6 activation allowing it to hydrolyze cGMP at a rate limited only by diffusional access to substrate (Chader et al. 1974, Goridis & Virmaux 1974, Miki et al. 1973). This event represents another amplification step in the phototransduction cascade wherein activated PDE6 hydrolyzes thousands of cGMP molecules per second. The decline in intracellular cGMP levels results in the closure of cyclic nucleotide gated cation channels (CNG channels). Mutations in the PDE6 subunits can cause retinitis pigmentosa or congenital stationary night blindness (https://sph.uth.edu/retnet/).
R-HSA-74065 (Reactome) The membrane associated cGMP phosphodiesterase 6 (PDE6) is a tetramer of two catalytic chains, alpha (PDE6A or PDEA) (Pittler et al. 1990) and beta (PDE6B or PDEB) (Weber et al. 1991), and two inhibitory gamma chains (PDE6G or PDEG) (Tuteja et al. 1990). Binding of an activated transducin alpha subunit (GNAT1-GTP) to PDE-gamma relaxes the inhibitory effect of the gamma subunit thereby activating the associated alpha or beta catalytic subunit. Because the binding of GNAT1-GTP to PDE-gamma is one to one, there is no amplification associated with this step. Active Gt alpha (GNAT-GTP) can be inactivated by a slow, intrinsic GTPase activity that hydrolyses GTP to GDP. Once GNAT1 has GDP bound, it no longer binds to the gamma subunit of PDE6 (PDE6-gamma) that then resumes inhibition of the catalytic subunit of PDE6. Some forms of autosomal recessive retinitis pigmentosa and congenital stationary night blindness are caused by mutations in PDE6 (https://sph.uth.edu/retnet/).

R-HSA-74101 (Reactome) The visual pigment rhodopsin consists of a seven transmembrane helix protein, opsin (RHO), to which an 11-cis-retinal (11cRAL) chromophore is bound as a protonated Schiff base (Hargrave et al. 1983, Nathans & Hogness 1984, Ovchinnikov et al. 1983). The covalent bond between opsin and its 11-cis-retinyl (11c-retinyl) ligand, which is unique among G protein coupled receptors, helps to confer extraordinary stability in darkness (Baylor et al. 1984). 11cRAL is an inverse agonist, that quenches the weak ability of opsin to activate transducin G protein (Gt). Upon photon absorption, the bound 11c-retinyl group isomerizes in a few hundred femtoseconds (Schoenlein et al. 1991) and with a high quantum efficiency of 0.7 (Dartnall 1968) to the bound all-trans-retinyl (at-retinyl) isomer. Then in the next few milliseconds, opsin undergoes a rearrangement in structure that renders it catalytically active (MII aka metarhodopsin II or R*) (Emeis et al. 1982). The isomerisation is a very fast photochemical process (femtoseconds) followed by slower events (Smith 2010).

Mutations in RHO can give rise to autosomal dominant or recessive forms of retinitis pigmentosa or autosomal dominant congenital stationary night blindness (https://sph.uth.edu/retnet/). Retinitis pigmentosa is a progressive form of blindness marked by an initial degeneration of rods, followed by the secondary loss of cones.
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions (Crouch and Klee 1980).
R-HSA-74615 (Reactome) In bovine experiments, phosphorylation of RGS9-1 (at Ser475, human site predicted to be at Ser478) by protein kinase C (PRKC, specifically the isozymes PRKCalpha and PRKCtheta) significantly decreased the affinity of RGS9-1 for its membrane anchor protein and GAP enhancer RGS9-1 anchor protein (R9S9BP). This represents a potential mechanism for feedback control of the photoresponse recovery in both rods and cones (Sokal et al. 2003, Balasubramanian et al. 2001, Hu et al. 2001).
R-HSA-74843 (Reactome) Once all-trans-retinol (atROL) enters the retinal pigment epithelium (RPE) and before esterification takes place, atROL binds to cellular retinol-binding protein 1 (RBP1) (Folli et al. 2001). The resultant complex (RBP1:atROL) serves as a substrate for lecithin retinol acyltransferase (LRAT), the main enzyme responsible for the esterification of atROL.
R-HSA-74872 (Reactome) Using NADP+ as cofactor, several members of the short-chain dehydrogenases/reductases (SDR) family can (reversibly) catalyse the oxidation of 11-cis-retinol (11cROL) to 11-cis-retinal (11cRAL) in retinal pigment epithelium (RPE) cells. Retinol dehydrogenases 10 and 11 (RDH10 and 11) are two such members utilizing the cofactor NADP+ (Wu et al. 2002, Kedishvili et al. 2002 respectively). Cellular retinaldehyde-binding protein (RLBP1), the protein bound to 11cRAL in RPE, is not present in photoreceptor cells.
R-HSA-74882 (Reactome) Once transducin alpha subunit (GNAT1) is deactivated by hydrolysis of bound GTP to GDP, it reassociates with transducin beta:gamma subunits (GNB1:GNGT1) to form inactive transducin (Gt-GDP). A stoichiometric overabundance of GNB1:GNGT1 facilitates the reassociation event. The details for this event were revealed in bovine experiments (Clark et al. 2006, Fung et al. 1981).
R-HSA-74885 (Reactome) The basal, "dark" levels of cGMP are restored as part of the recovery of light response by membrane guanylyl cyclases (GUCYs). Two variants, GUCY2D (Shyjan et al. 1992) and GUCY2F (Lowe et al. 1995), mediate the synthesis of cGMP from GTP. Unlike other membrane guanylyl cyclases, the rod types are not receptors for extracellular substances. Instead, GUCYs are regulated intracellularly by guanylyl cyclase activating proteins (GCAPs), this regulation being the most important negative feedback mechanism triggered by Ca2+ in light. There are three GCAPs in humans; GUCA1A, GUCA1B and GUCA1C (Subbaraya et al. 1994, Surguchov et al. 1997, Haeseleer et al. 1999). GCAPs are Ca2+ binding proteins. When Ca2+ concentration is high (in the "dark" condition), GCAPs bind Ca2+ and inhibit GUCYs. Conversely, when Ca2+ concentration is low (as in a light response), GCAPs release Ca2+ and bind Mg2+ in its place. With Mg2+ bound, GCAPs stimulate GUCY activity by an order of magnitude. This negative feedback operates rapidly to limit the amplitude and duration of the single photon response and to dampen the effects of spontaneous PDE activations. Mutations in GUCYD can give rise to Leber's congenital amaurosis or to cone-rod dystrophy (https://sph.uth.edu/retnet/).
R-HSA-74947 (Reactome) Loss of all-trans-retinal (atRAL) is followed by dissociation of arrestin (SAG) from p-RHO. RHO is then available for covalent binding to 11-cis-retinal (11cRAL), supplied by the retinal pigment epithelium, to regenerate rhodopsin. SAG is capable of binding weakly to rhodopsin, so the dissociation in some rhodopsins may occur after regeneration (Baumann & Bender 1973).
R-HSA-74948 (Reactome) Protein phosphatase 2A removes the phosphates from phosphorylated rhodopsin (p MII) and phosphorylated opsin (p-RHO) (Fowles et al. 1989, Palczewski et al. 1989a,b). A Ca2+ dependent opsin phosphatase is also present (Kutuzov & Bennett 1996). Serine/threonine protein phosphatases with EF hands (PPEF1 and 2) that share homology with Drosophila retinal degeneration C (rdgC) are expressed in retina and may be responsible (Huang & Honkanen 1998), there is no evidence for a physiological role in dephosphorylating rhodopsin. Once dephosphorylated, RHO can once again bind the chromophore 11 cis retinal (11cRAL), in readiness for the next photon response. Arrestin (S-antigen or SAG, Yamaki et al. 1988) binds to and sterically caps MII, preventing PPEF1 from dephosphorylating it.
R-HSA-8960973 (Reactome) Interphotoreceptor retinoid-binding protein (RBP3) is the major soluble protein in the interphotoreceptor matrix (IPM) (Liou et al. 1989, Fong & Bridges 1988). It is thought to shuttle 11-cis-retinal (11cRAL) between retinal pigment epithelium (RPE) and photoreceptor outer segments during the visual cycle but the mechanism is poorly understood (Gonzalez-Fernandez & Ghosh 2008). It is assumed cellular retinaldehyde-binding protein (RLBP1) must dissociate from 11cRAL before 11cRAL is transported as RLBP1 is not present in photoreceptor cells.
R-HSA-9656891 (Reactome) Human apo opsin proteins covalently bind the chromophore 11-cis-retinal (11cRAL) via a Schiff base linkage to a lysine residue in the seventh transmembrane alpha helix that is conserved in all known opsins (see review Shichida & Matsuyama 2009). The Schiff base linkage effectively results in an 11-cis-retinyl (11c-retinyl) group covalently linking to a lysine residue of opsins with subsequent loss of water. The three human cone opsins are Long Wavelength Sensitive Opsin (OPN1LW), Short Wavelength Sensitive Opsin (OPN1SW) and Middle Wavelength Sensitive Opsin (OPN1MW), sensing red, blue and green regions of the light spectrum, respectively (Nathans et al. 1986, Nathans et al. 1986b, Oprian et al. 1991).
R-HSA-9656893 (Reactome) Human apo opsin proteins covalently bind the chromophore 11-cis-retinal (11cRAL) via a Schiff base linkage to a lysine residue in the seventh transmembrane alpha helix that is conserved in all known opsins (see review Shichida & Matsuyama 2009). The Schiff base linkage effectively results in an 11-cis-retinyl (11c-retinyl) group covalently linking to a lysine residue of opsins with subsequent loss of water. The three human cone opsins are Long Wavelength Sensitive Opsin (OPN1LW), Short Wavelength Sensitive Opsin (OPN1SW) and Middle Wavelength Sensitive Opsin (OPN1MW), sensing red, blue and green regions of the light spectrum, respectively (Nathans et al. 1986, Nathans et al. 1986b, Oprian et al. 1991).
RBP1:atROLArrowR-HSA-74843 (Reactome)
RBP1:atROLR-HSA-2453855 (Reactome)
RBP1ArrowR-HSA-2453855 (Reactome)
RBP1R-HSA-74843 (Reactome)
RBP3mim-catalysisR-HSA-2454113 (Reactome)
RBP3mim-catalysisR-HSA-2464809 (Reactome)
RBP3mim-catalysisR-HSA-2465934 (Reactome)
RBP3mim-catalysisR-HSA-2465938 (Reactome)
RCVRN:Ca2+R-HSA-3229213 (Reactome)
RDH10,11mim-catalysisR-HSA-74872 (Reactome)
RDH12mim-catalysisR-HSA-2464822 (Reactome)
RDH5(1-318)-like Proteinsmim-catalysisR-HSA-2454081 (Reactome)
RDH8-like proteinsmim-catalysisR-HSA-2464803 (Reactome)
REHmim-catalysisR-HSA-2465941 (Reactome)
RGS9-1:GNB5:RGS9BPArrowR-HSA-2584246 (Reactome)
RGS9-1:GNB5:RGS9BPR-HSA-74615 (Reactome)
RHOArrowR-HSA-74948 (Reactome)
RHOR-HSA-2454118 (Reactome)
RLBP1:11cRALArrowR-HSA-2454081 (Reactome)
RLBP1:11cRALArrowR-HSA-74872 (Reactome)
RLBP1:11cRALR-HSA-8960973 (Reactome)
RLBP1:11cROLArrowR-HSA-2454264 (Reactome)
RLBP1:11cROLArrowR-HSA-2465926 (Reactome)
RLBP1:11cROLR-HSA-2454081 (Reactome)
RLBP1:11cROLR-HSA-2465919 (Reactome)
RLBP1:11cROLR-HSA-74872 (Reactome)
RLBP1:11cRPALMArrowR-HSA-2465919 (Reactome)
RLBP1:atROLArrowR-HSA-2465971 (Reactome)
RLBP1:atROLR-HSA-2465926 (Reactome)
RLBP1ArrowR-HSA-8960973 (Reactome)
RLBP1R-HSA-2454264 (Reactome)
RLBP1R-HSA-2465971 (Reactome)
RPE65mim-catalysisR-HSA-2453833 (Reactome)
S-farn-GNGT1ArrowR-HSA-2530501 (Reactome)
S-farn-GRK1:RCVRN:Ca2+ArrowR-HSA-3229213 (Reactome)
S-farn-GRK1:RCVRN:Ca2+TBarR-HSA-2581474 (Reactome)
S-farn-GRK1R-HSA-3229213 (Reactome)
SAGArrowR-HSA-74947 (Reactome)
SAGR-HSA-2581488 (Reactome)
SLC24A1mim-catalysisR-HSA-2514891 (Reactome)
STRA6R-HSA-2453876 (Reactome)
TTR:RBP4:STRA6ArrowR-HSA-2453863 (Reactome)
TTR:RBP4:atROL:STRA6ArrowR-HSA-2453876 (Reactome)
TTR:RBP4:atROL:STRA6R-HSA-2453863 (Reactome)
TTR:RBP4:atROLR-HSA-2453876 (Reactome)
acyl-CoAR-HSA-2534040 (Reactome)
at-retinyl-RHOArrowR-HSA-74101 (Reactome)
at-retinyl-RHOR-HSA-2581474 (Reactome)
at-retinyl-RHOmim-catalysisR-HSA-2485180 (Reactome)
at-retinyl-cone opsinsArrowR-HSA-2465917 (Reactome)
at-retinyl-cone opsinsR-HSA-2466085 (Reactome)
atRALArrowR-HSA-1467466 (Reactome)
atRALArrowR-HSA-2464810 (Reactome)
atRALArrowR-HSA-2466085 (Reactome)
atRALArrowR-HSA-2466718 (Reactome)
atRALArrowR-HSA-2632521 (Reactome)
atRALR-HSA-1467466 (Reactome)
atRALR-HSA-2464803 (Reactome)
atRALR-HSA-2464810 (Reactome)
atRALR-HSA-2464822 (Reactome)
atRALR-HSA-2465940 (Reactome)
atRALR-HSA-2466764 (Reactome)
atRALR-HSA-2466846 (Reactome)
atREsArrowR-HSA-2453855 (Reactome)
atREsR-HSA-2453833 (Reactome)
atROL isomerasemim-catalysisR-HSA-2465926 (Reactome)
atROLArrowR-HSA-2453863 (Reactome)
atROLArrowR-HSA-2464803 (Reactome)
atROLArrowR-HSA-2464809 (Reactome)
atROLArrowR-HSA-2464822 (Reactome)
atROLArrowR-HSA-2465938 (Reactome)
atROLArrowR-HSA-2465940 (Reactome)
atROLR-HSA-2464809 (Reactome)
atROLR-HSA-2465938 (Reactome)
atROLR-HSA-2465971 (Reactome)
atROLR-HSA-74843 (Reactome)
cGMP:CNG channelArrowR-HSA-74031 (Reactome)
cGMP:CNG channelR-HSA-2514865 (Reactome)
cGMP:CNG channelmim-catalysisR-HSA-2514867 (Reactome)
cGMPArrowR-HSA-2514865 (Reactome)
cGMPArrowR-HSA-74885 (Reactome)
cGMPR-HSA-74031 (Reactome)
cGMPR-HSA-74059 (Reactome)
hydroxydocosahexaenoic acidArrowR-HSA-6786239 (Reactome)
p-MII:SAGArrowR-HSA-2581488 (Reactome)
p-MII:SAGR-HSA-2632521 (Reactome)
p-MII:SAGTBarR-HSA-2485180 (Reactome)
p-MII:SAGTBarR-HSA-2581474 (Reactome)
p-MII:SAGTBarR-HSA-74948 (Reactome)
p-RHO:SAGArrowR-HSA-2632521 (Reactome)
p-RHO:SAGR-HSA-74947 (Reactome)
p-S334,338,343-RHOArrowR-HSA-74947 (Reactome)
p-S334,338,343-RHOR-HSA-74948 (Reactome)
p-S334,338,343-at-retinyl-RHOArrowR-HSA-2581474 (Reactome)
p-S334,338,343-at-retinyl-RHOR-HSA-2581488 (Reactome)
p-S334,338,343-at-retinyl-RHOTBarR-HSA-2485180 (Reactome)
p-S478-RGS9-1:GNB5:RGS9BPArrowR-HSA-74615 (Reactome)
unknown NATmim-catalysisR-HSA-2534040 (Reactome)
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