Tclin CNR1 Cannabinoid receptor 1

Protein Summary

Description

G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, PubMed:27768894, PubMed:27851727). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission (By similarity). In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca(2+) channels in a constitutive, as well as agonist-dependent manner (PubMed:17895407). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels leads to vasodilation and decreased vascular tone (By similarity). Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes (By similarity). In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake. Peripherally modulates energy metabolism (By similarity). In high carbohydrate diet-induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism (By similarity). In response to cannabinoid anandamide, elicits a proinflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion (By similarity). In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells (PubMed:23955712). Isoform 1: Binds both 2-AG and anandamide. Isoform 2: Only binds 2-AG with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 2 in assays measuring GTP binding to membranes. Isoform 3: Only binds 2-AG with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 3 in assays measuring GTP binding to membranes. This gene encodes one of two cannabinoid receptors. The cannabinoids, principally delta-9-tetrahydrocannabinol and synthetic analogs, are psychoactive ingredients of marijuana. The cannabinoid receptors are members of the guanine-nucleotide-binding protein (G-protein) coupled receptor family, which inhibit adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. The two receptors have been found to be involved in the cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana. Multiple transcript variants encoding two different protein isoforms have been described for this gene. [provided by RefSeq, May 2009]

Uniprot Accession IDs

• P21554
• B2R9T4
• E1P512
• Q13949
• Q495Z0
• Q4PLI4
• Q4VBM6
• Q5JVL5
• Q5UB37
• Q9UNN0
• CB-R

Gene Name

• CNR1

Ensembl ID

• ENST00000369499
• ENSP00000358511
• ENSG00000118432
• ENST00000369501
• ENSP00000358513
• ENST00000428600
• ENSP00000412192
• ENST00000468898
• ENSP00000420188
• ENST00000549890
• ENSP00000446819

Symbol

• CNR
• CB1
• CNR
• CB-R
• CB1A
• CB1R
• CANN6
• CB1K5

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	0.99
phenotype	0.99
chemical	0.88
microRNA	0.84
disease	0.82

Protein Classes

PANTHER Classes

Protein / Receptor / G-protein Coupled Receptor / Cannabinoid Receptor 1

DTO Classes

Protein / G-protein Coupled Receptor / Class A Rhodopsin Like / Cannabinoid Receptor / Cannabinoid Receptor 1

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: 1903.92   (req: < 5)

Gene RIFs: 380   (req: <= 3)

Antibodies: 546   (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: 1903.92   (req: >= 5)

Gene RIFs: 380   (req: > 3)

Antibodies: 546   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 38

Tchem

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

Active Ligands: 2329

Tclin

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

Active Drugs: 4

Expression Data (0 Tissues)

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No expression data found

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Related Tools (4)

Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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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 (4)

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1 – 4 of 4

dronabinol

CNR1Tclin GPCR

AGONIST pKi : 8.54

paracetamol

CNR1Tclin GPCR

AGONIST :

rimonabant

CNR1Tclin GPCR

ANTAGONIST pKi : 9.72

nabilone

CNR1Tclin GPCR

AGONIST pKi : 8.4

Active Ligands (2329)

Explore Active Ligands

1 – 10 of 2329

CHEMBL4476621

CNR1Tclin GPCR

pIC50 : 9.99

anandamide

CNR1Tclin GPCR

pKi : 7.05

cannabinol

CNR1Tclin GPCR

pKi : 7.89

HU-210

CNR1Tclin GPCR

pKi : 7.73

Taranbant

CNR1Tclin GPCR

pKi : 9.52

WIN55212-2

CNR1Tclin GPCR

pKi : 7.03

CP55940

CNR1Tclin GPCR

pKi : 7.89

CHEMBL3799603

CNR1Tclin GPCR

pIC50 : 9.2

BMS-202

CNR1Tclin GPCR

pIC50 : 7.75

arachidonyl-2-chloroethylamide

CNR1Tclin GPCR

pKi : 8.28

Protein-Protein Interactions (378)

Explore Interacting Targets

1 – 10 of 378

• See Interactions on String-DB

GPR55

Tclin

Family:  GPCR

Novelty:  0.00428199

Score:  0.989

Data Source:  STRINGDB

OPRL1

Tchem

Family:  GPCR

Novelty:  0.00186729

Score:  0.984

Data Source:  STRINGDB

DRD2

Tclin

Family:  GPCR

Novelty:  0.00033797

Score:  0.984

Data Source:  STRINGDB

OPRD1

Tclin

Family:  GPCR

Novelty:  0.00757692

Score:  0.983

Data Source:  STRINGDB

GPR18

Tchem

Family:  GPCR

Novelty:  0.0178347

Score:  0.969

Data Source:  STRINGDB

DRD3

Tclin

Family:  GPCR

Novelty:  0.00230028

Score:  0.966

Data Source:  STRINGDB

DRD4

Tchem

Family:  GPCR

Novelty:  0.00099622

Score:  0.965

Data Source:  STRINGDB

ADRA2A

Tclin

Family:  GPCR

Novelty:  0.00273659

Score:  0.962

Data Source:  STRINGDB

NPY

Tbio

Novelty:  0.00012637

Score:  0.961

Data Source:  STRINGDB

ADRA2C

Tclin

Family:  GPCR

Novelty:  0.00661399

Score:  0.961

Data Source:  STRINGDB

Nearest Tclin Targets

Nearest Tclin calculations are only available for targets with KEGG Pathway annotations.

Pathways (20)

Reactome (6)

KEGG (4)

PathwayCommons (2)

WikiPathways (8)

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	G alpha (i) signalling events	408 targets	R-HSA-418594
Reactome	GPCR downstream signalling	1152 targets	R-HSA-388396
Reactome	GPCR ligand binding	460 targets	R-HSA-500792
Reactome	Signal Transduction	2704 targets	R-HSA-162582

Name	Explore in Pharos	Explore in Source
Class A/1 (Rhodopsin-like receptors)	323 targets	R-HSA-373076
G alpha (i) signalling events	408 targets	R-HSA-418594
GPCR downstream signalling	1152 targets	R-HSA-388396
GPCR ligand binding	460 targets	R-HSA-500792
Signal Transduction	2704 targets	R-HSA-162582

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (47)

Functions (3)

Components (9)

Processes (35)

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10

1 – 3 of 3

GO Term	Evidence	Assigned by
cannabinoid receptor activity	Inferred from Direct Assay (IDA)	UniProtKB
drug binding	Inferred from Electronic Annotation (IEA)	Ensembl
voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels	Inferred from Electronic Annotation (IEA)	Ensembl

Disease Associations (null)

No disease associations found

GWAS Traits (1)

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1 – 1 of 1

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
gut microbiome measurement	EFO_0007874	1	1	0	5.5	0.2

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1 – 1 of 1

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
gut microbiome measurement	EFO_0007874	0	5.5	0.2

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UniProt Keyword Find Similar Targets

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3D-structure
Alternative splicing
Cell membrane
Cell projection
Complete proteome
G-protein coupled receptor
Glycoprotein
Lipoprotein
Membrane
Mitochondrion

GWAS Trait Find Similar Targets

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gut microbiome measurement

MGI Phenotype Find Similar Targets

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adipose tissue phenotype
behavior/neurological phenotype
cellular phenotype
digestive/alimentary phenotype
growth/size/body region phenotype
homeostasis/metabolism phenotype
integument phenotype
mortality/aging
nervous system phenotype
reproductive system phenotype

IDG Resources

No IDG generated resources found

Orthologs (13)

1 – 5 of 13

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	cannabinoid receptor 1	VGNC:12629	472066
Macaque	cannabinoid receptor 1		574142
Mouse	cannabinoid receptor 1 (brain)	MGI:104615	12801
Rat	cannabinoid receptor 1	RGD:2369	25248
Dog	cannabinoid receptor 1	VGNC:39426	481913

Species	Name	OMA	EggNOG	Inparanoid
Chimp	cannabinoid receptor 1
Macaque	cannabinoid receptor 1
Mouse	cannabinoid receptor 1 (brain)
Rat	cannabinoid receptor 1
Dog	cannabinoid receptor 1

Publication Statistics

PubMed Score 1903.92

PubMed score by year

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PubTator Score 2145.35

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Patents

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Related Publications

Text Mined References (433)

GeneRif Annotations (380)

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PMID	Year	Title