Tclin OPRM1 Mu-type opioid receptor

Protein Summary

Description

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 (PubMed:7905839, PubMed:7957926, PubMed:7891175, PubMed:12589820, PubMed:9689128). 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 (PubMed:7905839). 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 (PubMed:12068084). 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 whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects (PubMed:20525224). Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity (PubMed:16580639). This gene encodes one of at least three opioid receptors in humans; the mu opioid receptor (MOR). The MOR is the principal target of endogenous opioid peptides and opioid analgesic agents such as beta-endorphin and enkephalins. The MOR also has an important role in dependence to other drugs of abuse, such as nicotine, cocaine, and alcohol via its modulation of the dopamine system. The NM_001008503.2:c.118A>G allele has been associated with opioid and alcohol addiction and variations in pain sensitivity but evidence for it having a causal role is conflicting. Multiple transcript variants encoding different isoforms have been found for this gene. Though the canonical MOR belongs to the superfamily of 7-transmembrane-spanning G-protein-coupled receptors some isoforms of this gene have only 6 transmembrane domains. [provided by RefSeq, Oct 2013]

Uniprot Accession IDs

• P35372
• B0FXJ1
• B2R9S7
• B8Q1L7
• B8Q1L8
• B8Q1L9
• E7EWZ3
• G8XRH6
• G8XRH8
• Q12930
• Q4VWM1
• Q4VWM2
• Q4VWM3
• Q4VWM4
• Q4VWM6
• Q4VWX6
• Q5TDA1
• Q6UPP1
• Q6UQ80
• Q7Z2D8
• Q86V80
• Q8IWW3
• Q8IWW4
• Q9UCZ4
• Q9UN57
• M-OR-1

Gene Name

• OPRM1

Ensembl ID

• ENST00000229768
• ENSP00000229768
• ENSG00000112038
• ENST00000330432
• ENSP00000328264
• ENST00000337049
• ENSP00000338381
• ENST00000414028
• ENSP00000399359
• ENST00000419506
• ENSP00000403549
• ENST00000428397
• ENSP00000411903
• ENST00000434900
• ENSP00000394624
• ENST00000435918
• ENSP00000413752
• ENST00000452687
• ENSP00000410497
• ENST00000518759
• ENSP00000430260
• ENST00000519083
• ENSP00000431048
• ENST00000520708
• ENSP00000430876
• ENST00000522236
• ENSP00000429373
• ENST00000522555
• ENSP00000429719
• ENST00000522739
• ENSP00000428018
• ENST00000524150
• ENSP00000430575
• ENST00000524163
• ENSP00000430097

Symbol

• MOR1
• MOP
• MOR
• LMOR
• MOR1
• OPRM
• M-OR-1

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
drug	1
molecular function	1
biological process	0.99
ligand (chemical)	0.99
kinase	0.96

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 2784.86   (req: < 5)

Gene RIFs: 402   (req: <= 3)

Antibodies: 512   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 2784.86   (req: >= 5)

Gene RIFs: 402   (req: > 3)

Antibodies: 512   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 48

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 2476

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drugs: 42

Protein Sequence and Structure

Residue Counts

Protein Sequence

Show Full Sequence

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Target Illumination GWAS Analytics (TIGA)

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GENEVA

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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Approved Drugs (42)

Explore Approved Drugs

1 – 10 of 42

fentanyl

OPRM1Tclin GPCR

AGONIST pEC50 : 9

loperamide

OPRM1Tclin GPCR

AGONIST pKi : 8.82

nalfurafine

OPRM1Tclin GPCR

pKi : 8.22

alvimopan

OPRM1Tclin GPCR

ANTAGONIST pKi : 9.4

levorphanol

OPRM1Tclin GPCR

AGONIST pKi : 9.68

pethidine

OPRM1Tclin GPCR

AGONIST pKi : 6.04

naltrexone

OPRM1Tclin GPCR

ANTAGONIST pKi : 9.38

naloxone

OPRM1Tclin GPCR

ANTAGONIST pKi : 8.81

oliceridine

OPRM1Tclin GPCR

AGONIST pKi : 8.22

buprenorphine

OPRM1Tclin GPCR

PARTIAL AGONIST pKi : 8.29

Active Ligands (2476)

Explore Active Ligands

1 – 10 of 2476

CHEMBL4128926

OPRM1Tclin GPCR

pIC50 : 8.96

N-Desmethyl loperamide

OPRM1Tclin GPCR

pKi : 9.22

CHEMBL1644980

OPRM1Tclin GPCR

pKi : 7.16

SID11113698

OPRM1Tclin GPCR

pKi : 7.28

cebranopadol

OPRM1Tclin GPCR

pKi : 7.34

tramadol

OPRM1Tclin GPCR

pKi : 5.8

AT-076

OPRM1Tclin GPCR

pKi : 8.78

Buprenorphine

OPRM1Tclin GPCR

pKi : 8.8

CHEMBL3326224,CHEMBL3959398

OPRM1Tclin GPCR

pKi : 8.89

SCH221510

OPRM1Tclin GPCR

pKi : 7.19

Protein-Protein Interactions (456)

Explore Interacting Targets

1 – 10 of 456

• See Interactions on String-DB

ZFYVE26

Tbio

Novelty:  0.04897973

p_int:  0.999799451

p_ni:  0.000007509

p_wrong:  0.00019304

Score:  0.239

Data Source:  BioPlex,STRINGDB

MMS22L

Tbio

Novelty:  0.22570578

p_int:  0.9990965

p_ni:  0.000899655

p_wrong:  0.000003845

Data Source:  BioPlex

THADA

Tbio

Novelty:  0.06983966

p_int:  0.99831819

p_ni:  0.00168181

Data Source:  BioPlex

LPCAT3

Tbio

Family:  Enzyme

Novelty:  0.00485213

p_int:  0.997624847

p_ni:  0.002373546

p_wrong:  0.000001607

Data Source:  BioPlex

XPO6

Tbio

Novelty:  0.03229708

p_int:  0.997547629

p_ni:  0.00245237

Data Source:  BioPlex

XPO4

Tbio

Novelty:  0.01507446

p_int:  0.996145393

p_ni:  0.003854607

Data Source:  BioPlex

HTT

Tchem

Novelty:  0.00034051

p_int:  0.996145315

p_ni:  0.003854685

Score:  0.219

Data Source:  BioPlex,STRINGDB

BRAT1

Tbio

Novelty:  0.04039173

p_int:  0.995213743

p_ni:  0.004786256

Data Source:  BioPlex

MZT2B

Tdark

Novelty:  0.69469786

p_int:  0.994954521

p_ni:  0.004100907

p_wrong:  0.000944572

Data Source:  BioPlex

TUBGCP2

Tbio

Novelty:  0.01856674

p_int:  0.994884016

p_ni:  0.005115984

Data Source:  BioPlex

Pathways (28)

Reactome (18)

KEGG (3)

PathwayCommons (4)

WikiPathways (3)

Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Class A/1 (Rhodopsin-like receptors)	323 targets	R-HSA-373076
Reactome	Cytokine Signaling in Immune system	922 targets	R-HSA-1280215
Reactome	G alpha (i) signalling events	408 targets	R-HSA-418594
Reactome	G-protein activation	28 targets	R-HSA-202040
Reactome	GPCR downstream signalling	1152 targets	R-HSA-388396

Name	Explore in Pharos	Explore in Source
Class A/1 (Rhodopsin-like receptors)	323 targets	R-HSA-373076
Cytokine Signaling in Immune system	922 targets	R-HSA-1280215
G alpha (i) signalling events	408 targets	R-HSA-418594
G-protein activation	28 targets	R-HSA-202040
GPCR downstream signalling	1152 targets	R-HSA-388396

Gene Ontology Terms (65)

Functions (10)

Components (17)

Processes (38)

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10

1 – 10 of 10

GO Term	Evidence	Assigned by
G-protein alpha-subunit binding	Inferred from Direct Assay (IDA)	UniProtKB
beta-endorphin receptor activity	Inferred from Mutant Phenotype (IMP)	UniProtKB
G-protein beta-subunit binding	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
neuropeptide binding	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
G protein-coupled receptor activity	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
morphine receptor activity	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
voltage-gated calcium channel activity	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
filamin binding	Inferred from Electronic Annotation (IEA)	Ensembl
protein C-terminus binding	Inferred from Electronic Annotation (IEA)	Ensembl
protein domain specific binding	Inferred from Electronic Annotation (IEA)	Ensembl

GWAS Traits (9)

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5

1 – 5 of 9

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
chronic lymphocytic leukemia	EFO_0000095	2	2	0	1.2	55.8
diastolic blood pressure	EFO_0006336	1	1	1		48.5
IGF-1 measurement	EFO_0004627	1	1	1		42.3
body height	EFO_0004339	1	1	1		39.6
opioid use disorder	EFO_0010702	1	1	1		36.9

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 9

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
chronic lymphocytic leukemia	EFO_0000095	0	1.2	55.8
diastolic blood pressure	EFO_0006336	1		48.5
IGF-1 measurement	EFO_0004627	1		42.3
body height	EFO_0004339	1		39.6
opioid use disorder	EFO_0010702	1		36.9

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UniProt Keyword Find Similar Targets

No Header	No Header
Alternative splicing
Cell membrane
Cell projection
Complete proteome
Cytoplasm
Disulfide bond
Endosome
G-protein coupled receptor
Glycoprotein
Lipoprotein

GWAS Trait Find Similar Targets

No Header	No Header
body height
body mass index
chronic lymphocytic leukemia
comparative body size at age 10, self-reported
diastolic blood pressure
high density lipoprotein cholesterol measurement
IGF-1 measurement
opioid use disorder
testosterone measurement

MGI Phenotype Find Similar Targets

No Header	No Header
adipose tissue phenotype
behavior/neurological phenotype
cellular phenotype
digestive/alimentary phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
integument phenotype

Orthologs (13)

1 – 5 of 13

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	opioid receptor mu 1	VGNC:9593	472165
Macaque	opioid receptor mu 1		574141
Mouse	opioid receptor, mu 1	MGI:97441	18390
Rat	opioid receptor, mu 1	RGD:3234	25601
Horse	opioid receptor mu 1	VGNC:21045	100060029

Species	Name	OMA	EggNOG	Inparanoid
Chimp	opioid receptor mu 1
Macaque	opioid receptor mu 1