BioPAX pathway converted from "RCVRN:Ca2+ binds to and inhibits GRK1" in the Reactome database. LEFT-TO-RIGHT RCVRN:Ca2+ binds to and inhibits GRK1 Ca2+ and recoverin restrict GRK1 activity 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). Authored: Jassal, Bijay, 2013-03-26 Reviewed: Makino, C, 2013-04-11 Edited: Jassal, Bijay, 2013-03-26 S-farn-GRK1 S-fanesylated-Rhodopsin kinase Reactome DB_ID: 63140 photoreceptor disc membrane GENE ONTOLOGY GO:0097381 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. Homo sapiens NCBI Taxonomy 9606 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 http://www.reactome.org RCVRN:Ca2+ Reactome DB_ID: 3229219 cytosol GENE ONTOLOGY GO:0005829 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 additional information MI MI:0361 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 3229219 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=3229219 Reactome R-HSA-3229219 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-3229219.1 S-farn-GRK1:RCVRN:Ca2+ Reactome DB_ID: 3229193 1 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 Reactome Database ID Release 79 3229213 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=3229213 Reactome R-HSA-3229213 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-3229213.1 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 1999465 Pubmed 1991 A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy Polans, A S Buczyłko, J Crabb, J Palczewski, K J. Cell Biol. 112:981-9