ID OPRM_SAIBB Reviewed; 400 AA.
AC Q5IS84;
DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 15-FEB-2005, sequence version 1.
DT 24-JAN-2024, entry version 89.
DE RecName: Full=Mu-type opioid receptor;
DE Short=M-OR-1;
DE Short=MOR-1;
GN Name=OPRM1;
OS Saimiri boliviensis boliviensis (Bolivian squirrel monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Cebidae;
OC Saimiriinae; Saimiri.
OX NCBI_TaxID=39432;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=15620360; DOI=10.1016/j.cell.2004.11.040;
RA Dorus S., Vallender E.J., Evans P.D., Anderson J.R., Gilbert S.L.,
RA Mahowald M., Wyckoff G.J., Malcom C.M., Lahn B.T.;
RT "Accelerated evolution of nervous system genes in the origin of Homo
RT sapiens.";
RL Cell 119:1027-1040(2004).
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. Also activated by enkephalin peptides, such as Met-
CC enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-
CC enkephalin-Arg-Phe. Agonist binding to the receptor induces coupling to
CC an inactive GDP-bound heterotrimeric G-protein complex and subsequent
CC exchange of GDP for GTP in the G-protein alpha subunit leading to
CC dissociation of the G-protein complex with the free GTP-bound G-protein
CC alpha and 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 extent
CC to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They
CC mediate an array of downstream cellular responses, including inhibition
CC of adenylate cyclase activity and both N-type and L-type calcium
CC channels, activation of inward rectifying potassium channels, mitogen-
CC 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. {ECO:0000250|UniProtKB:P33535,
CC ECO:0000250|UniProtKB:P35372, ECO:0000250|UniProtKB:P42866}.
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:0000250|UniProtKB:P42866};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P42866}. Cell
CC projection, axon {ECO:0000250|UniProtKB:P97266}. Perikaryon
CC {ECO:0000250|UniProtKB:P97266}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:P97266}. Endosome
CC {ECO:0000250|UniProtKB:P97266}. Note=Is rapidly internalized after
CC agonist binding. {ECO:0000250|UniProtKB:P97266}.
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. Phosphorylation at Tyr-168 requires receptor activation, is
CC dependent on non-receptor protein tyrosine kinase Src and results in a
CC decrease in agonist efficacy by reducing G-protein coupling efficiency.
CC Phosphorylated on tyrosine residues; the phosphorylation is involved in
CC agonist-induced G-protein-independent receptor down-regulation.
CC Phosphorylation at Ser-377 is involved in G-protein-dependent but not
CC beta-arrestin-dependent activation of the ERK pathway (By similarity).
CC {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}.
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DR EMBL; AY665244; AAV74282.1; -; mRNA.
DR RefSeq; NP_001266908.1; NM_001279979.1.
DR AlphaFoldDB; Q5IS84; -.
DR SMR; Q5IS84; -.
DR STRING; 39432.ENSSBOP00000020184; -.
DR GlyCosmos; Q5IS84; 5 sites, No reported glycans.
DR Ensembl; ENSSBOT00000037002.1; ENSSBOP00000020175.1; ENSSBOG00000026674.1.
DR GeneID; 101042291; -.
DR CTD; 4988; -.
DR GeneTree; ENSGT00940000158236; -.
DR OrthoDB; 5393360at2759; -.
DR Proteomes; UP000233220; Unplaced.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0004979; F:beta-endorphin receptor activity; IEA:InterPro.
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:UniProtKB.
DR GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; ISS: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 CDD; cd15090; 7tmA_Mu_opioid_R; 1.
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; IPR000105; Mu_opioid_rcpt.
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; PR00537; MUOPIOIDR.
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 2: Evidence at transcript level;
KW Cell membrane; Cell projection; Disulfide bond; Endosome;
KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; Palmitate;
KW Phosphoprotein; Receptor; Reference proteome; Transducer; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..400
FT /note="Mu-type opioid receptor"
FT /id="PRO_0000246162"
FT TOPO_DOM 1..68
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 69..93
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 94..106
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 107..131
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 132..142
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 143..165
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 166..185
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 186..207
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 208..230
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 231..255
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 256..279
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 280..306
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 307..314
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TRANSMEM 315..338
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT TOPO_DOM 339..400
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT MOTIF 334..338
FT /note="NPxxY; plays a role in stabilizing the activated
FT conformation of the receptor"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT MOD_RES 168
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P33535"
FT MOD_RES 365
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42866"
FT MOD_RES 372
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P33535"
FT MOD_RES 377
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P33535"
FT MOD_RES 396
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P33535"
FT LIPID 353
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000255"
FT CARBOHYD 9
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 12
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 33
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 40
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 48
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 142..219
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
SQ SEQUENCE 400 AA; 44559 MW; 9AE5DEE957354023 CRC64;
MDSSAVPANA SNCTDPLAPS TCSPAPGPGS WVNLSHLDGN LSDPCGPNRT DLGGSDSPCP
PTGSPSMITA ITIMALYSIV CVVGLFGNFL VMYVIVRYTK MKTATNIYIF NLALADALAT
STLPFQSVNY LMGTWPFGTI LCKIVISIDY YNMFTSIFTL CTMSVDRYIA VCHPVKALDF
RTPRNAKIVN VCNWIISSAI GLPVMFMATT KYRQGSIDCT LTFSHPTWYW ENLLKICVFI
FAFIMPVLII TVCYGLMILR LKSVRMLSGS KEKDRNLRRI TRMVLVVVAV FIVCWTPIHI
YVIIKALVTI PETTFQTVSW HFCIALGYTN SCLNPVLYAF LDENFKRCFR EFCIPTPSAI
EQQNSARIRQ NTRDHPSTAN TVDRTNHQLE NLEAETAPLP
//
