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Protein

Cannabinoid receptor 1

Gene

CNR1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 delta9-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 Ca2+ channels in a constitutive, as well as agonist-dependent manner (PubMed:17895407). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca2+ 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).By similarity7 Publications
Isoform 1: Binds both 2-AG and anandamide.1 Publication
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.1 Publication
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.1 Publication

Miscellaneous

High-fat diet also increases the hepatic levels of CNR1 ligand anandamide, but not that of 2-arachidonoylglycerol.By similarity

GO - Molecular functioni

  • cannabinoid receptor activity Source: UniProtKB
  • drug binding Source: Ensembl

GO - Biological processi

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

ReactomeiR-HSA-373076. Class A/1 (Rhodopsin-like receptors).
R-HSA-418594. G alpha (i) signalling events.
SIGNORiP21554.

Protein family/group databases

TCDBi9.A.14.2.2. the g-protein-coupled receptor (gpcr) family.

Chemistry databases

SwissLipidsiSLP:000001607.

Names & Taxonomyi

Protein namesi
Recommended name:
Cannabinoid receptor 1
Short name:
CB-R
Short name:
CB1
Alternative name(s):
CANN6
Gene namesi
Name:CNR1
Synonyms:CNR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

EuPathDBiHostDB:ENSG00000118432.12.
HGNCiHGNC:2159. CNR1.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 116Extracellular2 PublicationsAdd BLAST116
Transmembranei117 – 142Helical; Name=12 PublicationsAdd BLAST26
Topological domaini143 – 154Cytoplasmic2 PublicationsAdd BLAST12
Transmembranei155 – 175Helical; Name=22 PublicationsAdd BLAST21
Topological domaini176 – 187Extracellular2 PublicationsAdd BLAST12
Transmembranei188 – 212Helical; Name=32 PublicationsAdd BLAST25
Topological domaini213 – 232Cytoplasmic2 PublicationsAdd BLAST20
Transmembranei233 – 255Helical; Name=42 PublicationsAdd BLAST23
Topological domaini256 – 273Extracellular2 PublicationsAdd BLAST18
Transmembranei274 – 299Helical; Name=52 PublicationsAdd BLAST26
Topological domaini300 – 344Cytoplasmic2 PublicationsAdd BLAST45
Transmembranei345 – 365Helical; Name=62 PublicationsAdd BLAST21
Topological domaini366 – 377Extracellular2 PublicationsAdd BLAST12
Transmembranei378 – 399Helical; Name=72 PublicationsAdd BLAST22
Topological domaini400 – 472Cytoplasmic2 PublicationsAdd BLAST73

Keywords - Cellular componenti

Cell membrane, Cell projection, Membrane, Mitochondrion, Mitochondrion outer membrane

Pathology & Biotechi

Involvement in diseasei

Obesity (OBESITY)1 Publication
The protein represented in this entry may be involved in disease pathogenesis. May contribute to the development of diet-induced obesity and several obesity-associated features, such as dyslipidemia and liver steatosis, regulating peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 inverse agonists have been shown to reduce body weight and improve metabolic abnormalities in obese subjects, although adverse neuropsychiatric effects, including anxiety, irritability, and depressed mood, halted their therapeutic development (PubMed:18177726). In obese mice, peripherally restricted CNR1 inverse agonists have been shown to normalize metabolic abnormalities, including insulin resistance and fatty liver, and to reverse leptin resistance.1 Publication
Disease descriptionA condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.
See also OMIM:601665

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi210T → A: 7-fold lower affinity for a synthetic agonist, CP55940, possibly due the stabilization of an inactive conformation. 1 Publication1
Mutagenesisi341 – 342LA → AL: Loss of activity, when assayed for GNAI1 GTPase stimulatory activity. 1 Publication2
Mutagenesisi415C → A: Loss of palmitoylation, marked loss of association with lipid rafts on the plasma membrane and loss of activity, when assayed for downstream GTP-binding and reduction in cAMP levels. 1 Publication1

Keywords - Diseasei

Obesity

Organism-specific databases

DisGeNETi1268.
MIMi601665. phenotype.
OpenTargetsiENSG00000118432.
PharmGKBiPA26681.

Chemistry databases

ChEMBLiCHEMBL218.
DrugBankiDB05750. AVE-1625.
DB05372. CP-945598.
DB00470. Dronabinol.
DB00486. Nabilone.
DB06155. Rimonabant.
DB05077. SLV319.
DB05201. V24343.
GuidetoPHARMACOLOGYi56.

Polymorphism and mutation databases

BioMutaiCNR1.
DMDMi115562.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000693141 – 472Cannabinoid receptor 1Add BLAST472

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi77N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi83N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi112N-linked (GlcNAc...) asparagineSequence analysis1
Lipidationi415S-palmitoyl cysteine1 Publication1
Modified residuei425PhosphoserineBy similarity1
Modified residuei429PhosphoserineBy similarity1

Post-translational modificationi

Palmitoylation at Cys-415 is important for recruitment at plasma membrane and lipid rafts and association with G protein alpha subunits.1 Publication

Keywords - PTMi

Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein

Proteomic databases

PaxDbiP21554.
PeptideAtlasiP21554.
PRIDEiP21554.

PTM databases

iPTMnetiP21554.
PhosphoSitePlusiP21554.
SwissPalmiP21554.

Expressioni

Tissue specificityi

Widely expressed, with highest levels in fetal and adult brain. Expression levels of isoform 2 and isoform 3 are much lower than those of isoform 1.1 Publication

Inductioni

Up-regulated by endocannabinoid anandamide.1 Publication

Gene expression databases

BgeeiENSG00000118432.
CleanExiHS_CNR1.
ExpressionAtlasiP21554. baseline and differential.
GenevisibleiP21554. HS.

Organism-specific databases

HPAiCAB005603.
HPA042256.

Interactioni

Subunit structurei

Interacts (via C-terminus) with CNRIP1; this interaction attenuates constitutive, but not agonist-dependent, inhibition of voltage-gated Ca2+ channels in neurons (PubMed:17895407). Associates with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) alpha-3/GNAI3 and G(o) alpha/GNAO1; palmitoylation is important for interaction with GNAI3 and GNAO1 (PubMed:12237474).2 Publications

Protein-protein interaction databases

BioGridi107668. 4 interactors.
DIPiDIP-61575N.
IntActiP21554. 1 interactor.
STRINGi9606.ENSP00000358511.

Chemistry databases

BindingDBiP21554.

Structurei

Secondary structure

1472
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi105 – 107Combined sources3
Helixi113 – 143Combined sources31
Helixi145 – 148Combined sources4
Helixi151 – 153Combined sources3
Helixi154 – 178Combined sources25
Helixi186 – 219Combined sources34
Turni221 – 223Combined sources3
Helixi224 – 227Combined sources4
Helixi230 – 249Combined sources20
Helixi250 – 253Combined sources4
Helixi257 – 260Combined sources4
Beta strandi266 – 268Combined sources3
Helixi273 – 300Combined sources28
Helixi333 – 367Combined sources35
Helixi375 – 400Combined sources26
Helixi402 – 409Combined sources8
Helixi411 – 414Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1LVQNMR-A338-346[»]
1LVRNMR-A338-346[»]
2B0YNMR-A400-414[»]
2KOENMR-A377-414[»]
2MZ2NMR-A400-414[»]
2MZ3NMR-A400-414[»]
2MZANMR-A400-414[»]
5TGZX-ray2.80A99-306[»]
A332-414[»]
5U09X-ray2.60A90-301[»]
A333-421[»]
ProteinModelPortaliP21554.
SMRiP21554.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP21554.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 23Required for mitochondrial localizationBy similarityAdd BLAST22

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3656. Eukaryota.
ENOG410XRW9. LUCA.
GeneTreeiENSGT00760000118804.
HOVERGENiHBG051045.
InParanoidiP21554.
KOiK04277.
OMAiTRMDIRL.
OrthoDBiEOG091G05O3.
PhylomeDBiP21554.
TreeFamiTF330052.

Family and domain databases

CDDicd15340. 7tmA_CB1. 1 hit.
InterProiView protein in InterPro
IPR000810. Canbinoid_rcpt_1.
IPR002230. Cnbnoid_rcpt.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
PANTHERiPTHR22750:SF57. PTHR22750:SF57. 1 hit.
PfamiView protein in Pfam
PF00001. 7tm_1. 1 hit.
PIRSFiPIRSF037995. Cnoid_rcpt_1. 1 hit.
PRINTSiPR00522. CANABINOID1R.
PR00362. CANNABINOIDR.
PR00237. GPCRRHODOPSN.
SMARTiView protein in SMART
SM01381. 7TM_GPCR_Srsx. 1 hit.
PROSITEiView protein in PROSITE
PS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P21554-1) [UniParc]FASTAAdd to basket
Also known as: Long

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL
60 70 80 90 100
TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSFK ENEENIQCGE
110 120 130 140 150
NFMDIECFMV LNPSQQLAIA VLSLTLGTFT VLENLLVLCV ILHSRSLRCR
160 170 180 190 200
PSYHFIGSLA VADLLGSVIF VYSFIDFHVF HRKDSRNVFL FKLGGVTASF
210 220 230 240 250
TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM WTIAIVIAVL
260 270 280 290 300
PLLGWNCEKL QSVCSDIFPH IDETYLMFWI GVTSVLLLFI VYAYMYILWK
310 320 330 340 350
AHSHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV
360 370 380 390 400
VLIICWGPLL AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR
410 420 430 440 450
SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA SVHRAAESCI
460 470
KSTVKIAKVT MSVSTDTSAE AL
Length:472
Mass (Da):52,858
Last modified:May 1, 1991 - v1
Checksum:i1D2E49061D12ABF2
GO
Isoform 2 (identifier: P21554-2) [UniParc]FASTAAdd to basket
Also known as: CB1a1 Publication, Short

The sequence of this isoform differs from the canonical sequence as follows:
     1-89: MKSILDGLAD...EFYNKSLSSF → MALQIPPSAPSPLTSCTWAQMTFSTKTS

Note: Dubious isoform. A putative downstream initiation AUG is used to produce isoform 2 (Ref.2). The use of the first AUG (same as isoform 1) gives a truncated protein of 36 AA.1 Publication
Show »
Length:411
Mass (Da):45,874
Checksum:iE3C31ACAB4066BC1
GO
Isoform 3 (identifier: P21554-3) [UniParc]FASTAAdd to basket
Also known as: CB1b1 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     22-54: Missing.

Show »
Length:439
Mass (Da):49,060
Checksum:iC80C6B8D640412C1
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti94E → G in AAH95513 (PubMed:15489334).Curated1
Sequence conflicti103M → I in AAH95513 (PubMed:15489334).Curated1
Sequence conflicti149C → R in AAH95513 (PubMed:15489334).Curated1
Sequence conflicti200F → L in AAD34320 (Ref. 5) Curated1
Sequence conflicti216I → V in AAD34320 (Ref. 5) Curated1
Sequence conflicti246V → A in AAD34320 (Ref. 5) Curated1
Sequence conflicti298L → P in AAH95513 (PubMed:15489334).Curated1
Sequence conflicti332P → S in AAI00972 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0018681 – 89MKSIL…SLSSF → MALQIPPSAPSPLTSCTWAQ MTFSTKTS in isoform 2. 1 PublicationAdd BLAST89
Alternative sequenceiVSP_01652922 – 54Missing in isoform 3. 1 PublicationAdd BLAST33

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X54937 mRNA. Translation: CAA38699.1.
X81120 mRNA. Translation: CAA57018.1.
X81121 mRNA. Translation: CAA57019.1.
AY766182 mRNA. Translation: AAV35030.1.
AF107262 mRNA. Translation: AAD34320.1.
U73304 Genomic DNA. Translation: AAB18200.1.
DQ067455 mRNA. Translation: AAY68486.1.
AY225225 Genomic DNA. Translation: AAO67710.1.
AL136096 Genomic DNA. Translation: CAB96726.1.
AL136096 Genomic DNA. Translation: CAI19916.1.
AK313908 mRNA. Translation: BAG36631.1.
CH471051 Genomic DNA. Translation: EAW48574.1.
CH471051 Genomic DNA. Translation: EAW48575.1.
CH471051 Genomic DNA. Translation: EAW48576.1.
BC074811 mRNA. Translation: AAH74811.1.
BC074812 mRNA. Translation: AAH74812.1.
BC095513 mRNA. Translation: AAH95513.1.
BC100968 mRNA. Translation: AAI00969.1.
BC100969 mRNA. Translation: AAI00970.1.
BC100970 mRNA. Translation: AAI00971.1.
BC100971 mRNA. Translation: AAI00972.1.
CCDSiCCDS5015.1. [P21554-1]
CCDS5016.2. [P21554-3]
PIRiS17595.
RefSeqiNP_001153698.1. NM_001160226.1. [P21554-1]
NP_001153730.1. NM_001160258.1. [P21554-1]
NP_001153731.1. NM_001160259.1. [P21554-1]
NP_057167.2. NM_016083.4. [P21554-1]
NP_149421.2. NM_033181.3. [P21554-3]
XP_006715393.1. XM_006715330.3. [P21554-1]
XP_011533726.1. XM_011535424.1. [P21554-1]
XP_011533727.1. XM_011535425.1. [P21554-1]
XP_011533728.1. XM_011535426.1. [P21554-1]
XP_011533730.1. XM_011535428.1. [P21554-1]
XP_016865727.1. XM_017010238.1. [P21554-1]
XP_016865728.1. XM_017010239.1. [P21554-1]
XP_016865729.1. XM_017010240.1. [P21554-1]
UniGeneiHs.75110.

Genome annotation databases

EnsembliENST00000369499; ENSP00000358511; ENSG00000118432. [P21554-1]
ENST00000369501; ENSP00000358513; ENSG00000118432. [P21554-1]
ENST00000428600; ENSP00000412192; ENSG00000118432. [P21554-1]
ENST00000468898; ENSP00000420188; ENSG00000118432. [P21554-3]
ENST00000549890; ENSP00000446819; ENSG00000118432. [P21554-1]
GeneIDi1268.
KEGGihsa:1268.

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiCNR1_HUMAN
AccessioniPrimary (citable) accession number: P21554
Secondary accession number(s): B2R9T4
, E1P512, Q13949, Q495Z0, Q4PLI4, Q4VBM6, Q5JVL5, Q5UB37, Q9UNN0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: May 1, 1991
Last modified: September 27, 2017
This is version 182 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  5. SIMILARITY comments
    Index of protein domains and families