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 29-MAY-2024, entry version 120. 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; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae; OC 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., Grandy D.K., RA 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 vivo."; RL Proc. Natl. Acad. Sci. U.S.A. 93:9241-9246(1996). CC -!- FUNCTION: Receptor for endogenous opioids such as beta-endorphin and CC endomorphin. Receptor for natural and synthetic opioids including CC morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and CC methadone (PubMed:8799185). Also activated by enkephalin peptides, such CC as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for CC Met-enkephalin-Arg-Phe. Agonist binding to the receptor induces CC coupling to an inactive GDP-bound heterotrimeric G-protein complex and CC subsequent exchange of GDP for GTP in the G-protein alpha subunit CC leading to dissociation of the G-protein complex with the free GTP- CC bound G-protein alpha and the G-protein beta-gamma dimer activating CC downstream cellular effectors. The agonist- and cell type-specific CC activity is predominantly coupled to pertussis toxin-sensitive G(i) and CC G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1, and to a lesser CC extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. CC They mediate an array of downstream cellular responses, including CC inhibition of adenylate cyclase activity and both N-type and L-type CC calcium channels, activation of inward rectifying potassium channels, CC mitogen-activated protein kinase (MAPK), phospholipase C (PLC), CC phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) CC and regulation of NF-kappa-B. Also couples to adenylate cyclase CC stimulatory G alpha proteins. The selective temporal coupling to G- CC proteins and subsequent signaling can be regulated by RGSZ proteins, CC such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK CC subfamily of Ser/Thr protein kinases and association with beta- CC arrestins is involved in short-term receptor desensitization. Beta- CC arrestins associate with the GPRK-phosphorylated receptor and uncouple CC it 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 of CC the ERK pathway occurs either in a G-protein-dependent or a beta- CC arrestin-dependent manner and is regulated by agonist-specific receptor CC phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) CC which dissociates from beta-arrestin at or near the plasma membrane and CC undergoes rapid recycling. Receptor down-regulation pathways are CC varying with the agonist and occur dependent or independent of G- CC protein coupling. Endogenous ligands induce rapid desensitization, CC endocytosis and recycling. Heterooligomerization with other GPCRs can CC modulate agonist binding, signaling and trafficking properties. CC Involved in neurogenesis (By similarity). CC {ECO:0000250|UniProtKB:P33535, ECO:0000250|UniProtKB:P35372, CC ECO:0000250|UniProtKB:P42866, ECO:0000269|PubMed:8799185}. CC -!- SUBUNIT: Forms homooligomers and heterooligomers with other GPCRs, such CC as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 (probably CC in dimeric forms). Interacts with heterotrimeric G proteins; CC interaction with a heterotrimeric complex containing GNAI1, GNB1 and CC GNG2 stabilizes the active conformation of the receptor and increases CC its affinity for endomorphin-2, the synthetic opioid peptide DAMGO and CC for morphinan agonists (By similarity). Interacts with PPL; the CC interaction disrupts agonist-mediated G-protein activation. Interacts CC (via C-terminus) with DNAJB4 (via C-terminus). Interacts with CC calmodulin; the interaction inhibits the constitutive activity of CC OPRM1; it 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 SYP CC and GNAS (By similarity). Interacts with RGS9, RGS17, RGS20, RGS4, CC 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 {ECO:0000269|PubMed:8799185}. CC Note=Is rapidly internalized after agonist binding. CC {ECO:0000269|PubMed:8799185}. CC -!- PTM: Phosphorylated. Differentially phosphorylated in basal and CC agonist-induced conditions. Agonist-mediated phosphorylation modulates CC receptor internalization. Phosphorylated by GRK2 in a agonist-dependent CC manner. Phosphorylated on tyrosine residues; the phosphorylation is CC involved in agonist-induced G-protein-independent receptor down- CC regulation (By similarity). {ECO:0000250}. CC -!- PTM: Phosphorylated. Differentially phosphorylated in basal and CC agonist-induced conditions. Agonist-mediated phosphorylation modulates CC receptor internalization. Phosphorylated by GRK2 in a agonist-dependent CC manner. Phosphorylated on tyrosine residues; the phosphorylation is CC involved in agonist-induced G-protein-independent receptor down- CC regulation. {ECO:0000250|UniProtKB:P33535}. CC -!- PTM: Ubiquitinated. A basal ubiquitination seems not to be related to CC degradation. Ubiquitination is increased upon formation of OPRM1:OPRD1 CC oligomers leading to proteasomal degradation; the ubiquitination is CC diminished by RTP4. {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 AlphaFoldDB; P97266; -. DR SMR; P97266; -. DR STRING; 10141.ENSCPOP00000015591; -. DR BindingDB; P97266; -. DR ChEMBL; CHEMBL4354; -. DR DrugCentral; P97266; -. DR eggNOG; KOG3656; Eukaryota. 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:0043204; C:perikaryon; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0045202; C:synapse; IEA:GOC. DR GO; GO:0004979; F:beta-endorphin receptor activity; IEA:TreeGrafter. 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:0031681; F:G-protein beta-subunit binding; IEA:TreeGrafter. DR GO; GO:0038047; F:morphine receptor activity; ISS:UniProtKB. DR GO; GO:0042923; F:neuropeptide binding; IEA:TreeGrafter. 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:UniProtKB. DR GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; IDA:UniProtKB. 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: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 Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR001418; Opioid_rcpt. DR PANTHER; PTHR24229:SF7; MU-TYPE OPIOID RECEPTOR; 1. DR PANTHER; PTHR24229; NEUROPEPTIDES RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00384; OPIOIDR. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. 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; Endosome; G-protein coupled receptor; KW Lipoprotein; Membrane; Palmitate; Phosphoprotein; Receptor; KW Reference proteome; Transducer; Transmembrane; Transmembrane helix; KW Ubl conjugation. FT CHAIN <1..>98 FT /note="Mu-type opioid receptor" FT /id="PRO_0000069971" FT TOPO_DOM <1..9 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P42866" FT TRANSMEM 10..34 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:P42866" FT TOPO_DOM 35..45 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:P42866" FT TRANSMEM 46..68 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:P42866" FT TOPO_DOM 69..88 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P42866" FT TRANSMEM 89..>98 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:P42866" FT MOD_RES 71 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P33535" FT NON_TER 1 FT NON_TER 98 SQ SEQUENCE 98 AA; 11161 MW; BEDB096924E0B9BE CRC64; YTKMKTATNI YIFNLALADA LATSTLPFQS VNYLMGTWPF GTILCKIVIS IDYYNMFTSI FTLCTMSVDR YIAVCHPVKA LDFRTPRNAK TVNVCNWI //