ID OPRM_CAVPO Reviewed; 98 AA. AC P97266; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 13-FEB-2019, entry version 104. DE RecName: Full=Mu-type opioid receptor; DE Short=M-OR-1; DE Short=MOR-1; DE Flags: Fragment; GN Name=OPRM1; OS Cavia porcellus (Guinea pig). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; OC Hystricomorpha; Caviidae; Cavia. OX NCBI_TaxID=10141; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Ronnekleiv O.K., Bosch M.A., Cunningham M.J., Wagner E.J., RA Grandy D.K., Kelly M.J.; RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases. RN [2] RP SUBCELLULAR LOCATION, RECEPTOR INTERNALIZATION, AND FUNCTION. RX PubMed=8799185; DOI=10.1073/pnas.93.17.9241; RA Sternini C., Spann M., Anton B., Keith D.E. Jr., Bunnett N.W., RA von Zastrow M., Evans C., Brecha N.C.; RT "Agonist-selective endocytosis of mu opioid receptor by neurons in RT vivo."; RL Proc. Natl. Acad. Sci. U.S.A. 93:9241-9246(1996). CC -!- FUNCTION: Receptor for endogenous opioids such as beta-endorphin CC and endomorphin. Receptor for natural and synthetic opioids CC including morphine, heroin, DAMGO, fentanyl, etorphine, CC buprenorphin and methadone (PubMed:8799185). Agonist binding to CC the receptor induces coupling to an inactive GDP-bound CC heterotrimeric G-protein complex and subsequent exchange of GDP CC for GTP in the G-protein alpha subunit leading to dissociation of CC the G-protein complex with the free GTP-bound G-protein alpha and CC the G-protein beta-gamma dimer activating downstream cellular CC effectors. The agonist- and cell type-specific activity is CC predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G CC alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1, and to a lesser CC extent to pertussis toxin-insensitive G alpha proteins GNAZ and CC GNA15. They mediate an array of downstream cellular responses, CC including inhibition of adenylate cyclase activity and both N-type CC and L-type calcium channels, activation of inward rectifying CC potassium channels, mitogen-activated protein kinase (MAPK), CC phospholipase C (PLC), phosphoinositide/protein kinase (PKC), CC phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. CC Also couples to adenylate cyclase stimulatory G alpha proteins. CC The selective temporal coupling to G-proteins and subsequent CC signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 CC and RGS4. Phosphorylation by members of the GPRK subfamily of CC Ser/Thr protein kinases and association with beta-arrestins is CC involved in short-term receptor desensitization. Beta-arrestins CC associate with the GPRK-phosphorylated receptor and uncouple it CC from the G-protein thus terminating signal transduction. The CC phosphorylated receptor is internalized through endocytosis via CC clathrin-coated pits which involves beta-arrestins. The activation CC of the ERK pathway occurs either in a G-protein-dependent or a CC beta-arrestin-dependent manner and is regulated by agonist- CC specific receptor phosphorylation. Acts as a class A G-protein CC coupled receptor (GPCR) which dissociates from beta-arrestin at or CC near the plasma membrane and undergoes rapid recycling. Receptor CC down-regulation pathways are varying with the agonist and occur CC dependent or independent of G-protein coupling. Endogenous ligands CC induce rapid desensitization, endocytosis and recycling. CC Heterooligomerization with other GPCRs can modulate agonist CC binding, signaling and trafficking properties. Involved in CC neurogenesis (By similarity). {ECO:0000250|UniProtKB:P33535, CC ECO:0000250|UniProtKB:P35372, ECO:0000250|UniProtKB:P42866, CC ECO:0000269|PubMed:8799185}. CC -!- SUBUNIT: Forms homooligomers and heterooligomers with other GPCRs, CC such as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 CC (probably in dimeric forms). Interacts with heterotrimeric G CC proteins; interaction with a heterotrimeric complex containing CC GNAI1, GNB1 and GNG2 stabilizes the active conformation of the CC receptor and increases its affinity for endomorphin-2, the CC synthetic opioid peptide DAMGO and for morphinan agonists (By CC similarity). Interacts with PPL; the interaction disrupts agonist- CC mediated G-protein activation. Interacts (via C-terminus) with CC DNAJB4 (via C-terminus). Interacts with calmodulin; the CC interaction inhibits the constitutive activity of OPRM1; it CC abolishes basal and attenuates agonist-stimulated G-protein CC coupling. Interacts with FLNA, PLD2, RANBP9 and WLS and GPM6A (By CC similarity). Interacts with RTP4 (By similarity). Interacts with CC SYP and GNAS (By similarity). Interacts with RGS9, RGS17, RGS20, CC RGS4, PPP1R9B and HINT1. {ECO:0000250|UniProtKB:P33535, CC ECO:0000250|UniProtKB:P35372, ECO:0000250|UniProtKB:P42866}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:8799185}; CC Multi-pass membrane protein {ECO:0000269|PubMed:8799185}. Cell CC projection, axon {ECO:0000269|PubMed:8799185}. Perikaryon CC {ECO:0000269|PubMed:8799185}. Cell projection, dendrite CC {ECO:0000269|PubMed:8799185}. Endosome CC {ECO:0000269|PubMed:8799185}. Note=Is rapidly internalized after CC agonist binding. {ECO:0000269|PubMed:8799185}. CC -!- PTM: Phosphorylated. Differentially phosphorylated in basal and CC agonist-induced conditions. Agonist-mediated phosphorylation CC modulates receptor internalization. Phosphorylated by GRK2 in a CC agonist-dependent manner. Phosphorylated on tyrosine residues; the CC phosphorylation is involved in agonist-induced G-protein- CC independent receptor down-regulation (By similarity). CC {ECO:0000250}. CC -!- PTM: Phosphorylated. Differentially phosphorylated in basal and CC agonist-induced conditions. Agonist-mediated phosphorylation CC modulates receptor internalization. Phosphorylated by GRK2 in a CC agonist-dependent manner. Phosphorylated on tyrosine residues; the CC phosphorylation is involved in agonist-induced G-protein- CC independent receptor down-regulation. CC {ECO:0000250|UniProtKB:P33535}. CC -!- PTM: Ubiquitinated. A basal ubiquitination seems not to be related CC to degradation. Ubiquitination is increased upon formation of CC OPRM1:OPRD1 oligomers leading to proteasomal degradation; the CC ubiquitination is diminished by RTP4. CC {ECO:0000250|UniProtKB:P42866}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U67928; AAB39617.1; -; Genomic_DNA. DR ProteinModelPortal; P97266; -. DR SMR; P97266; -. DR STRING; 10141.ENSCPOP00000017994; -. DR BindingDB; P97266; -. DR ChEMBL; CHEMBL4354; -. DR eggNOG; KOG3656; Eukaryota. DR eggNOG; ENOG410XRW9; LUCA. DR HOGENOM; HOG000230486; -. DR InParanoid; P97266; -. DR Proteomes; UP000005447; Unassembled WGS sequence. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0004930; F:G protein-coupled receptor activity; ISS:UniProtKB. DR GO; GO:0001965; F:G-protein alpha-subunit binding; ISS:UniProtKB. DR GO; GO:0038047; F:morphine receptor activity; ISS:UniProtKB. DR GO; GO:0005245; F:voltage-gated calcium channel activity; ISS:UniProtKB. DR GO; GO:0007197; P:adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway; ISS:GO_Central. DR GO; GO:0043951; P:negative regulation of cAMP-mediated signaling; ISS:UniProtKB. DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; ISS:UniProtKB. DR GO; GO:0045019; P:negative regulation of nitric oxide biosynthetic process; ISS:UniProtKB. DR GO; GO:0061358; P:negative regulation of Wnt protein secretion; ISS:UniProtKB. DR GO; GO:0038003; P:opioid receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0050769; P:positive regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:2000310; P:regulation of NMDA receptor activity; ISS:UniProtKB. DR GO; GO:0019233; P:sensory perception of pain; ISS:UniProtKB. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR001418; Opioid_rcpt. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00384; OPIOIDR. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 3: Inferred from homology; KW Cell membrane; Cell projection; Complete proteome; Endosome; KW G-protein coupled receptor; Lipoprotein; Membrane; Palmitate; KW Phosphoprotein; Receptor; Reference proteome; Transducer; KW Transmembrane; Transmembrane helix; Ubl conjugation. FT CHAIN <1 >98 Mu-type opioid receptor. FT /FTId=PRO_0000069971. FT TOPO_DOM <1 9 Cytoplasmic. FT {ECO:0000250|UniProtKB:P42866}. FT TRANSMEM 10 34 Helical; Name=2. FT {ECO:0000250|UniProtKB:P42866}. FT TOPO_DOM 35 45 Extracellular. FT {ECO:0000250|UniProtKB:P42866}. FT TRANSMEM 46 68 Helical; Name=3. FT {ECO:0000250|UniProtKB:P42866}. FT TOPO_DOM 69 88 Cytoplasmic. FT {ECO:0000250|UniProtKB:P42866}. FT TRANSMEM 89 >98 Helical; Name=4. FT {ECO:0000250|UniProtKB:P42866}. FT MOD_RES 71 71 Phosphotyrosine. FT {ECO:0000250|UniProtKB:P33535}. FT NON_TER 1 1 FT NON_TER 98 98 SQ SEQUENCE 98 AA; 11161 MW; BEDB096924E0B9BE CRC64; YTKMKTATNI YIFNLALADA LATSTLPFQS VNYLMGTWPF GTILCKIVIS IDYYNMFTSI FTLCTMSVDR YIAVCHPVKA LDFRTPRNAK TVNVCNWI //