UniProt functional annotation for P42866



	UniProt functional annotation for P42866

UniProt code: P42866.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK- phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta- arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 9 is involved in morphine-induced scratching and seems to cross- activate GRPR in response to morphine. {ECO:0000269|PubMed:10842167, ECO:0000269|PubMed:16682964, ECO:0000269|PubMed:21422164, ECO:0000269|PubMed:22437502, ECO:0000269|PubMed:26245379, ECO:0000269|PubMed:7797593, ECO:0000269|PubMed:9037090}.

Subunit: Forms homooligomers and heterooligomers with other GPCRs, such as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 (probably in dimeric forms) (PubMed:10842167, PubMed:12270145, PubMed:18836069, PubMed:21422164). Interacts with heterotrimeric G proteins; interaction with a heterotrimeric complex containing GNAI1, GNB1 and GNG2 stabilizes the active conformation of the receptor and increases its affinity for endomorphin-2, the synthetic opioid peptide DAMGO and for morphinan agonists (PubMed:26245379). Interacts with PPL; the interaction disrupts agonist-mediated G-protein activation. Interacts (via C-terminus) with DNAJB4 (via C-terminus). Interacts with calmodulin; the interaction inhibits the constitutive activity of OPRM1; it abolishes basal and attenuates agonist-stimulated G-protein coupling. Interacts with FLNA, PLD2, RANBP9 and WLS and GPM6A (By similarity). Interacts with RTP4 (PubMed:18836069). Interacts with SYP and GNAS (By similarity). Interacts with RGS9, RGS17, RGS20, RGS4, PPP1R9B and HINT1 (PubMed:15827571, PubMed:17725581, PubMed:18439408, PubMed:21153910). Isoform 9 interacts with GRPR (PubMed:22000021). {ECO:0000250|UniProtKB:P33535, ECO:0000250|UniProtKB:P35372, ECO:0000269|PubMed:10842167, ECO:0000269|PubMed:12270145, ECO:0000269|PubMed:15827571, ECO:0000269|PubMed:17725581, ECO:0000269|PubMed:18439408, ECO:0000269|PubMed:18836069, ECO:0000269|PubMed:21153910, ECO:0000269|PubMed:21422164, ECO:0000269|PubMed:22000021, ECO:0000269|PubMed:22437502, ECO:0000269|PubMed:26245379}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:12642578, ECO:0000269|PubMed:22437502, ECO:0000269|PubMed:7797593}; Multi-pass membrane protein {ECO:0000269|PubMed:12642578, ECO:0000269|PubMed:22437502, ECO:0000269|PubMed:26245379, ECO:0000269|PubMed:7797593}. Cell projection, axon {ECO:0000250|UniProtKB:P97266}. Perikaryon {ECO:0000250|UniProtKB:P97266}. Cell projection, dendrite {ECO:0000250|UniProtKB:P97266}. Endosome {ECO:0000250|UniProtKB:P97266}. Note=Is rapidly internalized after agonist binding. {ECO:0000250|UniProtKB:P97266}.

Ptm: Phosphorylated. Differentially phosphorylated in basal and agonist-induced conditions. Agonist-mediated phosphorylation modulates receptor internalization. Phosphorylated by GRK2 in a agonist-dependent manner. Phosphorylation at Tyr-166 requires receptor activation, is dependent on non-receptor protein tyrosine kinase Src and results in a decrease in agonist efficacy by reducing G-protein coupling efficiency. Phosphorylated on tyrosine residues; the phosphorylation is involved in agonist-induced G-protein-independent receptor down-regulation. Phosphorylation at Ser-375 is involved in G-protein-dependent but not beta-arrestin-dependent activation of the ERK pathway. {ECO:0000250|UniProtKB:P33535}.

Ptm: Ubiquitinated. A basal ubiquitination seems not to be related to degradation. Ubiquitination is increased upon formation of OPRM1:OPRD1 oligomers leading to proteasomal degradation; the ubiquitination is diminished by RTP4. {ECO:0000269|PubMed:18836069}.

Disruption phenotype: During adult neurogenesis in hippocampus, increased numbers of granule cells maturing into neurons, larger granule cell layers and increased numbers of granule cells. {ECO:0000269|PubMed:16682964}.

Similarity: Belongs to the G-protein coupled receptor 1 family. {ECO:0000255|PROSITE-ProRule:PRU00521}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK- phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta- arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 9 is involved in morphine-induced scratching and seems to cross- activate GRPR in response to morphine. {ECO:0000269\|PubMed:10842167, ECO:0000269\|PubMed:16682964, ECO:0000269\|PubMed:21422164, ECO:0000269\|PubMed:22437502, ECO:0000269\|PubMed:26245379, ECO:0000269\|PubMed:7797593, ECO:0000269\|PubMed:9037090}.


Subunit:		Forms homooligomers and heterooligomers with other GPCRs, such as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 (probably in dimeric forms) (PubMed:10842167, PubMed:12270145, PubMed:18836069, PubMed:21422164). Interacts with heterotrimeric G proteins; interaction with a heterotrimeric complex containing GNAI1, GNB1 and GNG2 stabilizes the active conformation of the receptor and increases its affinity for endomorphin-2, the synthetic opioid peptide DAMGO and for morphinan agonists (PubMed:26245379). Interacts with PPL; the interaction disrupts agonist-mediated G-protein activation. Interacts (via C-terminus) with DNAJB4 (via C-terminus). Interacts with calmodulin; the interaction inhibits the constitutive activity of OPRM1; it abolishes basal and attenuates agonist-stimulated G-protein coupling. Interacts with FLNA, PLD2, RANBP9 and WLS and GPM6A (By similarity). Interacts with RTP4 (PubMed:18836069). Interacts with SYP and GNAS (By similarity). Interacts with RGS9, RGS17, RGS20, RGS4, PPP1R9B and HINT1 (PubMed:15827571, PubMed:17725581, PubMed:18439408, PubMed:21153910). Isoform 9 interacts with GRPR (PubMed:22000021). {ECO:0000250\|UniProtKB:P33535, ECO:0000250\|UniProtKB:P35372, ECO:0000269\|PubMed:10842167, ECO:0000269\|PubMed:12270145, ECO:0000269\|PubMed:15827571, ECO:0000269\|PubMed:17725581, ECO:0000269\|PubMed:18439408, ECO:0000269\|PubMed:18836069, ECO:0000269\|PubMed:21153910, ECO:0000269\|PubMed:21422164, ECO:0000269\|PubMed:22000021, ECO:0000269\|PubMed:22437502, ECO:0000269\|PubMed:26245379}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:12642578, ECO:0000269\|PubMed:22437502, ECO:0000269\|PubMed:7797593}; Multi-pass membrane protein {ECO:0000269\|PubMed:12642578, ECO:0000269\|PubMed:22437502, ECO:0000269\|PubMed:26245379, ECO:0000269\|PubMed:7797593}. Cell projection, axon {ECO:0000250\|UniProtKB:P97266}. Perikaryon {ECO:0000250\|UniProtKB:P97266}. Cell projection, dendrite {ECO:0000250\|UniProtKB:P97266}. Endosome {ECO:0000250\|UniProtKB:P97266}. Note=Is rapidly internalized after agonist binding. {ECO:0000250\|UniProtKB:P97266}.
Ptm:		Phosphorylated. Differentially phosphorylated in basal and agonist-induced conditions. Agonist-mediated phosphorylation modulates receptor internalization. Phosphorylated by GRK2 in a agonist-dependent manner. Phosphorylation at Tyr-166 requires receptor activation, is dependent on non-receptor protein tyrosine kinase Src and results in a decrease in agonist efficacy by reducing G-protein coupling efficiency. Phosphorylated on tyrosine residues; the phosphorylation is involved in agonist-induced G-protein-independent receptor down-regulation. Phosphorylation at Ser-375 is involved in G-protein-dependent but not beta-arrestin-dependent activation of the ERK pathway. {ECO:0000250\|UniProtKB:P33535}.
Ptm:		Ubiquitinated. A basal ubiquitination seems not to be related to degradation. Ubiquitination is increased upon formation of OPRM1:OPRD1 oligomers leading to proteasomal degradation; the ubiquitination is diminished by RTP4. {ECO:0000269\|PubMed:18836069}.
Disruption phenotype:		During adult neurogenesis in hippocampus, increased numbers of granule cells maturing into neurons, larger granule cell layers and increased numbers of granule cells. {ECO:0000269\|PubMed:16682964}.
Similarity:		Belongs to the G-protein coupled receptor 1 family. {ECO:0000255\|PROSITE-ProRule:PRU00521}.