Reviewed, UniProtKB/Swiss-Prot P34972 (CNR2_HUMAN)

Names and origin

Protein names

Recommended name:
    Cannabinoid receptor 2
      Short name=CB-2
      Short name=hCB2
      Short name=CB2
Alternative name(s):
    CX5

Gene names

Name:

CNR2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	360 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis. Ref.10 Ref.14 Ref.15 Ref.19
Subcellular location	Cell membrane; Multi-pass membrane protein. Cell projection › dendrite By similarity. Perikaryon By similarity. Note: Localizes to apical dendrite of pyramidal neurons By similarity.
Tissue specificity	Preferentially expressed in cells of the immune system with higher expression in B cells and NK cells (at protein level). Expressed in skin in suprabasal layers and hair follicles (at protein level). Highly expressed in tonsil and to a lower extent in spleen, peripheral blood mononuclear cells, and thymus. Ref.17 could not detect expression in normal brain. Expressed in brain by perivascular microglial cells and dorsal root glanglion sensory neurons (at protein level). Ref.19 Ref.8 Ref.12 Ref.16 Ref.17 Ref.18
Post-translational modification	Constitutively phosphorylated on Ser-352; phosphorylation increases cell internalization and desensitizes the receptor. Ref.9
Involvement in disease	Allelic variation at the CB2 locus is associated to genetic predisposition for depression in Japanese populations.
Sequence similarities	Belongs to the G-protein coupled receptor 1 family.

Ontologies

Keywords
Biological process	Inflammatory response
Cellular component	Cell membrane Cell projection Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Glycoprotein Phosphoprotein
Gene Ontology (GO)
Biological process	G-protein signaling, coupled to cyclic nucleotide second messenger Traceable author statement. Source: ProtInc behavior Ref.8 Traceable author statement. Source: ProtInc immune response Ref.8 Traceable author statement. Source: ProtInc inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	dendrite Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Traceable author statement. Source: ProtInc perikaryon Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	cannabinoid receptor activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 360	360	Cannabinoid receptor 2		PRO_0000069323
Regions
	Topological domain	1 – 33	33	Extracellular Potential
	Transmembrane	34 – 59	26	1 Potential
	Topological domain	60 – 71	12	Cytoplasmic Potential
	Transmembrane	72 – 92	21	2 Potential
	Topological domain	93 – 104	12	Extracellular Potential
	Transmembrane	105 – 129	25	3 Potential
	Topological domain	130 – 149	20	Cytoplasmic Potential
	Transmembrane	150 – 172	23	4 Potential
	Topological domain	173 – 188	16	Extracellular Potential
	Transmembrane	189 – 214	26	5 Potential
	Topological domain	215 – 246	32	Cytoplasmic Potential
	Transmembrane	247 – 267	21	6 Potential
	Topological domain	268 – 279	12	Extracellular Potential
	Transmembrane	280 – 301	22	7 Potential
	Topological domain	302 – 360	59	Cytoplasmic Potential
Amino acid modifications
	Modified residue	335	1	Phosphoserine By similarity
	Modified residue	336	1	Phosphoserine By similarity
	Modified residue	352	1	Phosphoserine Ref.9
	Glycosylation	11	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	63	1	Q → R Associated with depresssion in Japanese population. dbSNP rs2501432. Ref.7 Ref.20		VAR_054310
	Natural variant	316	1	H → Y: dbSNP rs2229579. Ref.7 Ref.20 Ref.4		VAR_029209
Experimental info
	Mutagenesis	109	1	K → A: No effect on agonist binding. Affects cannabinoid agonist binding; when associated with G-112. Ref.10
	Mutagenesis	109	1	K → R: No effect on agonist binding. Ref.10
	Mutagenesis	112	1	S → G: Affects cannabinoid agonist binding; when associated with A-109. Ref.10
	Mutagenesis	130	1	D → A: Loss of ligand binding. Alters agonist-induced inhibitory effect on adenylate cyclase. Ref.14
	Mutagenesis	131	1	R → A: No effect on ligand binding. Alters agonist-induced inhibitory effect on adenylate cyclase. Ref.14
	Mutagenesis	201	1	L → P: Abolishes ligand binding and agonist-induced inhibitory effect on adenylate cyclase. Ref.13
	Mutagenesis	207	1	Y → A: Abolishes agonist-induced inhibitory effect on adenylate cyclase. No effect on ligand binding. Ref.13
	Mutagenesis	244	1	A → E: Loss of ligand binding. Alters agonist-induced inhibitory effect on adenylate cyclase. Ref.14
	Sequence conflict	173	1	T → A in AAH95545. Ref.7
	Sequence conflict	307	1	R → H in AAH69722. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	P34972-1 [UniParc]. Last modified February 1, 1994. Version 1. Checksum: A7ECF68C16E7514B	FASTA	360	39,681
	10 20 30 40 50 60 MEECWVTEIA NGSKDGLDSN PMKDYMILSG PQKTAVAVLC TLLGLLSALE NVAVLYLILS 70 80 90 100 110 120 SHQLRRKPSY LFIGSLAGAD FLASVVFACS FVNFHVFHGV DSKAVFLLKI GSVTMTFTAS 130 140 150 160 170 180 VGSLLLTAID RYLCLRYPPS YKALLTRGRA LVTLGIMWVL SALVSYLPLM GWTCCPRPCS 190 200 210 220 230 240 ELFPLIPNDY LLSWLLFIAF LFSGIIYTYG HVLWKAHQHV ASLSGHQDRQ VPGMARMRLD 250 260 270 280 290 300 VRLAKTLGLV LAVLLICWFP VLALMAHSLA TTLSDQVKKA FAFCSMLCLI NSMVNPVIYA 310 320 330 340 350 360 LRSGEIRSSA HHCLAHWKKC VRGLGSEAKE EAPRSSVTET EADGKITPWP DSRDLDLSDC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular characterization of a peripheral receptor for cannabinoids." Munro S., Thomas K.L., Abu-Shaar M. Nature 365:61-65(1993) [PubMed: 7689702] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cannabinoid receptors and their genes." Bruess M., Boenisch H. Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. Tissue: Blood.
[3]	"Isolation of complete coding sequence for cannabinoid receptor 2 (CNR2)." Warren C.N., Aronstam R.S., Sharma S.V. Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Amplification and cloning of human cannabinoid receptor 2 gene from Asiatic origin." Saravanan T., Chugh A., Kant R. Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT TYR-316. Tissue: Blood.
[5]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS ARG-63 AND TYR-316. Tissue: Brain.
[8]	"Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations." Galiegue S., Mary S., Marchand J., Dussossoy D., Carriere D., Carayon P., Bouaboula M., Shire D., Le Fur G., Casellas P. Eur. J. Biochem. 232:54-61(1995) [PubMed: 7556170] [Abstract] Cited for: TISSUE SPECIFICITY.
[9]	"Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse agonist SR 144528. Implications for receptor biological responses." Bouaboula M., Dussossoy D., Casellas P. J. Biol. Chem. 274:20397-20405(1999) [PubMed: 10400664] [Abstract] Cited for: PHOSPHORYLATION AT SER-352, SUBCELLULAR LOCATION.
[10]	"Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity." Tao Q., McAllister S.D., Andreassi J., Nowell K.W., Cabral G.A., Hurst D.P., Bachtel K., Ekman M.C., Reggio P.H., Abood M.E. Mol. Pharmacol. 55:605-613(1999) [PubMed: 10051546] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF LYS-109 AND SER-112.
[11]	"Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells." Sugiura T., Kondo S., Kishimoto S., Miyashita T., Nakane S., Kodaka T., Suhara Y., Takayama H., Waku K. J. Biol. Chem. 275:605-612(2000) [PubMed: 10617657] [Abstract] Cited for: IDENTIFICATION OF 2-ARACHIDONOYLGLYCEROL AS AN ENDOGENOUS LIGAND.
[12]	"Presence and regulation of the endocannabinoid system in human dendritic cells." Matias I., Pochard P., Orlando P., Salzet M., Pestel J., Di Marzo V. Eur. J. Biochem. 269:3771-3778(2002) [PubMed: 12153574] [Abstract] Cited for: TISSUE SPECIFICITY.
[13]	"Absence of a conserved proline and presence of a conserved tyrosine in the CB2 cannabinoid receptor are crucial for its function." Song Z.H., Feng W. FEBS Lett. 531:290-294(2002) [PubMed: 12417328] [Abstract] Cited for: MUTAGENESIS OF LEU-201 AND TYR-207.
[14]	"Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor." Feng W., Song Z.H. Biochem. Pharmacol. 65:1077-1085(2003) [PubMed: 12663043] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-130; ARG-131 AND ALA-244.
[15]	"2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism." Kishimoto S., Gokoh M., Oka S., Muramatsu M., Kajiwara T., Waku K., Sugiura T. J. Biol. Chem. 278:24469-24475(2003) [PubMed: 12711605] [Abstract] Cited for: FUNCTION.
[16]	"Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors." Casanova M.L., Blazquez C., Martinez-Palacio J., Villanueva C., Fernandez-Acenero M.J., Huffman J.W., Jorcano J.L., Guzman M. J. Clin. Invest. 111:43-50(2003) [PubMed: 12511587] [Abstract] Cited for: TISSUE SPECIFICITY.
[17]	"Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains." Benito C., Nunez E., Tolon R.M., Carrier E.J., Rabano A., Hillard C.J., Romero J. J. Neurosci. 23:11136-11141(2003) [PubMed: 14657172] [Abstract] Cited for: TISSUE SPECIFICITY.
[18]	"Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study." Nunez E., Benito C., Pazos M.R., Barbachano A., Fajardo O., Gonzalez S., Tolon R.M., Romero J. Synapse 53:208-213(2004) [PubMed: 15266552] [Abstract] Cited for: TISSUE SPECIFICITY.
[19]	"Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons." Anand U., Otto W.R., Sanchez-Herrera D., Facer P., Yiangou Y., Korchev Y., Birch R., Benham C., Bountra C., Chessell I.P., Anand P. Pain 138:667-680(2008) [PubMed: 18692962] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[20]	"Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects." Onaivi E.S., Ishiguro H., Gong J.-P., Patel S., Meozzi P.A., Myers L., Perchuk A., Mora Z., Tagliaferro P.A., Gardner E., Brusco A., Akinshola B.E., Hope B., Lujilde J., Inada T., Iwasaki S., Macharia D., Teasenfitz L., Arinami T., Uhl G.R. PLoS ONE 3:E1640-E1640(2008) [PubMed: 18286196] [Abstract] Cited for: VARIANTS ARG-63 AND TYR-316, POSSIBLE INVOLVEMENT IN DEPRESSION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X74328 mRNA. Translation: CAA52376.1. AJ430063 mRNA. Translation: CAD22548.1. AJ430064 Genomic DNA. Translation: CAD22549.1. AY242132 Genomic DNA. Translation: AAO92299.1. AM156854 mRNA. Translation: CAJ42137.1. AM156855 mRNA. Translation: CAJ42138.1. AM156856 mRNA. Translation: CAJ42139.1. AL590609 Genomic DNA. Translation: CAI14799.1. CH471134 Genomic DNA. Translation: EAW95099.1. BC069722 mRNA. Translation: AAH69722.1. BC074767 mRNA. Translation: AAH74767.1. BC095545 mRNA. Translation: AAH95545.1.
IPI	IPI00003060.
PIR	S36750.
RefSeq	NP_001832.1.
UniGene	Hs.73037
3D structure databases
ModBase	Search...
Protein family/group databases
GPCRDB	Search...
PTM databases
PhosphoSite	P34972.
Genome annotation databases
Ensembl	ENSG00000188822. Homo sapiens. [Contig view]
GeneID	1269.
KEGG	hsa:1269.
Organism-specific databases
GeneCards	GC01M024069.
H-InvDB	HIX0028631.
HGNC	HGNC:2160. CNR2.
HPA	CAB009719.
MIM	605051. gene.
PharmGKB	PA26682.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P34972.
HOVERGEN	P34972.
OMA	P34972. DRYLCLR.
Gene expression databases
ArrayExpress	P34972.
Bgee	P34972.
CleanEx	HS_CNR2.
GermOnline	ENSG00000188822. Homo sapiens.
Family and domain databases
InterPro	IPR000276. 7TM_GPCR_Rhodpsn. IPR001551. Canbinoid_rcpt_2. IPR002230. Cnbnoid_rcpt. IPR017452. GPCR_Rhodpsn_supfam. [Graphical view]
PANTHER	PTHR22750:SF11. Canbinoid_rcpt_2. 1 hit.
Pfam	PF00001. 7tm_1. 1 hit. [Graphical view]
PRINTS	PR00523. CANABINOID2R. PR00362. CANNABINOIDR. PR00237. GPCRRHODOPSN.
PROSITE	PS00237. G_PROTEIN_RECEP_F1_1. 1 hit. PS50262. G_PROTEIN_RECEP_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
BindingDB	P34972.
DrugBank	DB00486. Nabilone.
NextBio	5139.
SOURCE	Search...

Entry information

Entry name

CNR2_HUMAN

Accession

Primary (citable) accession number: P34972
Secondary accession number(s): Q4VBK8 , Q5JRH7, Q6B0G7, Q6NSY0

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	February 1, 1994
Last modified:	June 16, 2009
This is version 82 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)