BioPAX pathway converted from "GRK1,4,7 phosphorylate MII to p-MII" in the Reactome database. LEFT-TO-RIGHT 2.7.11.14 GRK1,4,7 phosphorylate MII to p-MII GRK1 phosphorylates MII to p-S334,S338,S343-MII 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).<br><br>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).<br><br>Certain mutations in GRK1 cause Oguchi type 2 disease, a rare, recessive form of congenital stationary night blindness (https://sph.uth.edu/retnet/). Authored: Jassal, Bijay, 2012-11-13 Reviewed: Makino, C, 2013-04-11 Edited: Jassal, Bijay, 2012-11-13 R* at-retinyl-RHO at-retinyl-Rhodopsin MII activated rhodopsin Reactome DB_ID: 5205901 photoreceptor disc membrane GENE ONTOLOGY GO:0097381 UniProt:P08100 RHO RHO OPN2 FUNCTION Photoreceptor required for image-forming vision at low light intensity (PubMed:8107847, PubMed:7846071). Required for photoreceptor cell viability after birth (PubMed:2215617, PubMed:12566452). Light-induced isomerization of the chromophore 11-cis-retinal to all-trans-retinal triggers a conformational change that activates signaling via G-proteins (PubMed:8107847, PubMed:28524165, PubMed:26200343, PubMed:28753425). Subsequent receptor phosphorylation mediates displacement of the bound G-protein alpha subunit by the arrestin SAG and terminates signaling (PubMed:28524165, PubMed:26200343).SUBUNIT Homodimer (By similarity). May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO (By similarity). Interacts with GRK1 (PubMed:28524165). Interacts (phosphorylated form) with SAG (PubMed:28524165, PubMed:26200343, PubMed:28753425). Interacts with GNAT1 (PubMed:26200343). Interacts with GNAT3. SAG and G-proteins compete for a common binding site (PubMed:26200343). Interacts with PRCD; the interaction promotes PRCD stability (By similarity).TISSUE SPECIFICITY Rod shaped photoreceptor cells which mediate vision in dim light.PTM Phosphorylated on some or all of the serine and threonine residues present in the C-terminal region (By similarity). After activation by light, phosphorylated by GRK1 (in vitro) (PubMed:28524165).PTM Contains one covalently linked retinal chromophore. Upon light absorption, the covalently bound 11-cis-retinal is converted to all-trans-retinal. After hydrolysis of the Schiff base and release of the covalently bound all-trans-retinal, active rhodopsin is regenerated by binding of a fresh molecule of 11-cis-retinal(PubMed:12566452).SIMILARITY Belongs to the G-protein coupled receptor 1 family. Opsin subfamily. Homo sapiens NCBI Taxonomy 9606 UniProt P08100 296 EQUAL N6-retinylidene-L-lysine MOD MOD:00129 1 EQUAL 348 EQUAL Reactome Database ID Release 79 5205901 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5205901 Reactome R-HSA-5205901 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5205901.1 Reactome http://www.reactome.org ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 79 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 additional information MI MI:0361 3 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 79 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 3 RHO p-S334,338,343-at-retinyl-RHO Rhodopsin OPSD_HUMAN Reactome DB_ID: 5205903 334 EQUAL O-phospho-L-serine MOD MOD:00046 338 EQUAL 343 EQUAL 296 EQUAL N6-3,4-didehydroretinylidene-L-lysine MOD MOD:00317 1 EQUAL 348 EQUAL Reactome Database ID Release 79 5205903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5205903 Reactome R-HSA-5205903 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5205903.1 ACTIVATION Converted from EntitySet in Reactome GRK1,4,7 Reactome DB_ID: 6787798 GRK4-1 G protein-coupled receptor kinase 4 ecNumber2.7.11.16/ecNumber GRK4_HUMAN Reactome DB_ID: 6787795 UniProt:P32298-1 GRK4 GRK4 GPRK2L GPRK4 FUNCTION Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2.ACTIVITY REGULATION Inhibited by heparin.SUBUNIT Interacts with DRD3.TISSUE SPECIFICITY Isoform 1, isoform 2, isoform 3, and isoform 4 are expressed in testis. Isoform 4 is expressed in myometrium.PTM Palmitoylated.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. UniProt Isoform P32298-1 1 EQUAL 578 EQUAL Reactome Database ID Release 79 6787795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6787795 Reactome R-HSA-6787795 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6787795.1 GRK7 G protein-coupled receptor kinase 7 ecNumber evidence="8"2.7.11.14/ecNumber ecNumber2.7.11.16/ecNumber GRK7_HUMAN Reactome DB_ID: 6787797 UniProt:Q8WTQ7 GRK7 GRK7 GPRK7 FUNCTION Retina-specific kinase involved in the shutoff of the photoresponse and adaptation to changing light conditions via cone opsin phosphorylation, including rhodopsin (RHO).ACTIVITY REGULATION Inhibited by phosphorylation of Ser-36.SUBUNIT Interacts (when prenylated) with PDE6D; this promotes release from membranes.TISSUE SPECIFICITY Retinal cones, outer and inner segments.PTM Autophosphorylated in vitro at Ser-490. Phosphorylation at Ser-36 is regulated by light and activated by cAMP.MISCELLANEOUS Although the protein is present in a diversity of vertebrates ranging from bony fish to mammals, the mouse and rat orthologous proteins do not exist.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. UniProt Q8WTQ7 1 EQUAL 550 EQUAL Reactome Database ID Release 79 6787797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6787797 Reactome R-HSA-6787797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6787797.1 S-farn-GRK1 S-fanesylated-Rhodopsin kinase Reactome DB_ID: 63140 UniProt:Q15835 GRK1 GRK1 RHOK FUNCTION Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade (PubMed:15946941). This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination (By similarity). May play a role in the maintenance of the outer nuclear layer in the retina (By similarity).ACTIVITY REGULATION Inhibited by RCVRN, which prevents the interaction between GRK1 and RHO (By similarity). Inhibition is calcium-dependent (By similarity). Inhibited by phosphorylation of Ser-21.SUBUNIT Interacts (via N-terminus) with RCVRN (via C-terminus); the interaction is Ca(2+)-dependent (By similarity). Interacts (when prenylated) with PDE6D; this promotes release from membranes (By similarity). May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO (By similarity).TISSUE SPECIFICITY Retinal-specific. Expressed in rods and cones cells.PTM Autophosphorylated, Ser-21 is a minor site of autophosphorylation compared to Ser-491 and Thr-492 (By similarity). Phosphorylation at Ser-21 is regulated by light and activated by cAMP.PTM Farnesylation is required for full activity.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. UniProt Q15835 560 EQUAL S-farnesyl-L-cysteine MOD MOD:00111 1 EQUAL 560 EQUAL Reactome Database ID Release 79 63140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63140 Reactome R-HSA-63140 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63140.1 Reactome Database ID Release 79 6787798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6787798 Reactome R-HSA-6787798 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6787798.1 GENE ONTOLOGY GO:0050254 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 79 2581483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2581483 Reactome Database ID Release 79 2581474 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2581474 Reactome R-HSA-2581474 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2581474.3 1387789 Pubmed 1992 Isolation of human retinal genes: recoverin cDNA and gene Murakami, A Yajima, T Inana, G Biochem. Biophys. Res. Commun. 187:234-44 3164688 Pubmed 1988 The sequence of human retinal S-antigen reveals similarities with alpha-transducin. Yamaki, K Tsuda, M Shinohara, T FEBS Lett 234:39-43 11754336 Pubmed 2001 Characterization of human GRK7 as a potential cone opsin kinase Chen, CK Zhang, K Church-Kopish, J Huang, W Zhang, H Chen, Y J Frederick, J M Baehr, W Mol. Vis. 7:305-13 22658984 Pubmed 2012 Speed, sensitivity, and stability of the light response in rod and cone photoreceptors: facts and models Korenbrot, Juan I Prog Retin Eye Res 31:442-66 18803695 Pubmed 2008 Phosphorylation of GRK7 by PKA in cone photoreceptor cells is regulated by light Osawa, Shoji Jo, Rebecca Weiss, Ellen R J. Neurochem. 107:1314-24 8812493 Pubmed 1996 Characterization and chromosomal localization of the gene for human rhodopsin kinase Khani, S C Abitbol, M Yamamoto, S Maravic-Magovcevic, I Dryja, T P Genomics 35:571-6 8626439 Pubmed 1996 Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants Premont, R T Macrae, A D Stoffel, R H Chung, N Pitcher, J A Ambrose, C Inglese, J MacDonald, M E Lefkowitz, RJ J. Biol. Chem. 271:6403-10 20430952 Pubmed 2010 Lessons from photoreceptors: turning off G-protein signaling in living cells Burns, Marie E Pugh, Edward N Physiology (Bethesda) 25:72-84 15946941 Pubmed 2005 Phosphorylation of GRK1 and GRK7 by cAMP-dependent protein kinase attenuates their enzymatic activities Horner, Thierry J Osawa, Shoji Schaller, Michael D Weiss, Ellen R J. Biol. Chem. 280:28241-50 INHIBITION Reactome Database ID Release 79 5603166 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5603166 Reactome R-HSA-5603166 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5603166.1 p-MII:SAG Reactome DB_ID: 2581511 SAG S-arrestin Retinal S-antigen 48 kDa protein Rod photoreceptor arrestin Reactome DB_ID: 50320 UniProt:P10523 SAG SAG FUNCTION Binds to photoactivated, phosphorylated RHO and terminates RHO signaling via G-proteins by competing with G-proteins for the same binding site on RHO (By similarity). May play a role in preventing light-dependent degeneration of retinal photoreceptor cells (PubMed:9565049).SUBUNIT Monomer. Homodimer. Homotetramer (PubMed:21288033). Interacts with RHO (via the phosphorylated C-terminus) (PubMed:26200343, PubMed:28753425).TISSUE SPECIFICITY Detected in retina, in the proximal portion of the outer segment of rod photoreceptor cells (at protein level).DOMAIN The C-terminus interferes with binding to non-phosphorylated RHO. Interaction with phosphorylated RHO triggers displacement of the C-terminus and leads to a conformation change that mediates high-affinity RHO binding.SIMILARITY Belongs to the arrestin family. UniProt P10523 1 EQUAL 405 EQUAL Reactome Database ID Release 79 50320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=50320 Reactome R-HSA-50320 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-50320.1 1 1 Reactome Database ID Release 79 2581511 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2581511 Reactome R-HSA-2581511 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2581511.1 INHIBITION Reactome Database ID Release 79 3223247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3223247 Reactome R-HSA-3223247 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3223247.1 S-farn-GRK1:RCVRN:Ca2+ Reactome DB_ID: 3229193 1 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74016 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 79 74016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016 Reactome R-ALL-74016 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74016.3 COMPOUND C00076 1 RCVRN Recoverin Cancer associated retinopathy protein CAR protein Reactome DB_ID: 62913 UniProt:P35243 RCVRN RCVRN RCV1 FUNCTION Acts as a calcium sensor and regulates phototransduction of cone and rod photoreceptor cells (By similarity). Modulates light sensitivity of cone photoreceptor in dark and dim conditions (By similarity). In response to high Ca(2+) levels induced by low light levels, prolongs RHO/rhodopsin activation in rod photoreceptor cells by binding to and inhibiting GRK1-mediated phosphorylation of RHO/rhodopsin (By similarity). Plays a role in scotopic vision/enhances vision in dim light by enhancing signal transfer between rod photoreceptors and rod bipolar cells (By similarity). Improves rod photoreceptor sensitivity in dim light and mediates response of rod photoreceptors to facilitate detection of change and motion in bright light (By similarity).SUBUNIT Homodimer; disulfide-linked (By similarity). Homodimerization is caused by prolonged intense illumination (By similarity). May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO (By similarity). Interacts (via C-terminus) with GRK1 (via N-terminus); the interaction is Ca(2+)-dependent (By similarity).TISSUE SPECIFICITY Retina and pineal gland.DOMAIN EF-hand 2 and EF-hand 3 domains are the low-affinity and the high-affinity calcium binding sites, respectively. EF-hand 1 and EF-hand 4 domains do not bind calcium due to substitutions that disrupt their respective Ca(2+) binding loops. The cooperative binding of calcium to the EF-hand 2 domain following EF-hand 3 domain calcium binding requires myristoylation (By similarity). Calcium binding to the 2 EF-hand domains induces exposure of the myristoyl group through a protein conformation change, this process known as the calcium-myristoyl switch facilitates binding to photoreceptor cell membranes (By similarity).PTM The N-terminal glycine is linked to one of four different types of acyl groups. The most abundant is myristoleate (14:1), but 14:0, 14:2, and 12:0 acyl residues are also present (By similarity). The Ca(2+) induced exposure of the myristoyl group, known as the calcium-myristoyl switch, promotes RCVRN binding to the photoreceptor cell membranes only when intracellular Ca(2+) concentration is high (By similarity).PTM Oxidation on Cys-39 occurs in response to prolonged intense illumination and results in the formation of disulfide homodimers, and to a lesser extent disulfide-linked heterodimers.SIMILARITY Belongs to the recoverin family. UniProt P35243 2 EQUAL 200 EQUAL Reactome Database ID Release 79 62913 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=62913 Reactome R-HSA-62913 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-62913.1 1 Reactome Database ID Release 79 3229193 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3229193 Reactome R-HSA-3229193 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3229193.1 INHIBITION Reactome Database ID Release 79 3223249 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3223249 Reactome R-HSA-3223249 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3223249.1