Cannabinoid receptor 2

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(Redirected from
Cannabinoid receptor type 2
)
"CNR2" redirects here. For the airport in Ontario, Canada, see Innerkip Aerodrome.
CNR2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000188822

ENSMUSG00000062585

UniProt

P34972

P47936

RefSeq (mRNA)

NM_001841

NM_009924
NM_001305278

RefSeq (protein)

NP_001832

NP_001292207
NP_034054

Location (UCSC)Chr 1: 23.87 – 23.91 MbChr 4: 135.62 – 135.65 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The cannabinoid receptor 2 (CB2), is a

phytocannabinoids (plant cannabinoids).[5][7] The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).[6]

CB2 was

cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor 1 (CB1) receptor, discovered in 1990.[8]
The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.

Structure

The CB2 receptor is encoded by the CNR2 gene.

amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor.[9]

As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains,

downregulation following repeated agonist application,[9]
perhaps causing the receptor to become less responsive to particular ligands.

The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity.

lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue.[12] These interactions induce a conformational change in the receptor structure, which triggers the activation of various intracellular signaling pathways. Further research is needed to determine the exact molecular mechanisms of signaling pathway activation.[12]

Mechanism

Like the CB1 receptors, CB2 receptors inhibit the activity of

agonists acting through the Gβγ subunit ultimately results in changes in cell migration.[18]

Five recognized

N-arachidonoyl-dopamine (NADA).[19] Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG activates the MAPK-ERK pathway, while noladin inhibits adenylyl cyclase.[13]

Expression

Dispute

Originally it was thought that the CB2 receptor was only expressed in peripheral tissue while the CB1 receptor is the endogenous receptor on neurons. Recent work with immunohistochemical staining has shown expression within neurons. Subsequently, it was shown that CB2 knock out mice produced the same immunohistochemical staining, indicating the presence of the CB2 receptor where none was expressed. This has created a long history of debate as to whether the CB2 receptor is expressed in the CNS. A new mouse model was described in 2014 that expresses a fluorescent protein whenever CB2 is expressed within a cell. This has the potential to resolve questions about the expression of CB2 receptors in various tissues.[20]

Immune system

Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the

T-cells.[6][10]

Brain

Further investigation into the expression patterns of the CB2 receptors revealed that CB2 receptor gene transcripts are also expressed in the brain, though not as densely as the CB1 receptor and located on different cells.[22] Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on microglia.[21][23] The CB2 receptor is expressed in some neurons within the central nervous system (e.g.; the brainstem), but the expression is very low.[24][25] CB2s are expressed on some rat retinal cell types.[26] Functional CB2 receptors are expressed in neurons of the ventral tegmental area and the hippocampus, arguing for a widespread expression and functional relevance in the CNS and in particular in neuronal signal transmission.[27][28]

Gastrointestinal system

CB2 receptors are also found throughout the

inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis.[30][31] The role of endocannabinoids, as such, play an important role in inhibiting unnecessary immune action upon the natural gut flora. Dysfunction of this system, perhaps from excess FAAH activity, could result in IBD. CB2 activation may also have a role in the treatment of irritable bowel syndrome.[32] Cannabinoid receptor agonists reduce gut motility in IBS patients.[33]

Peripheral nervous system

Application of CB2-specific antagonists has found that these receptors are also involved in mediating analgesic effects in the peripheral nervous system. However, these receptors are not expressed by nociceptive sensory neurons, and at present are believed to exist on an undetermined, non-neuronal cell. Possible candidates include mast cells, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli.[8]

Function

Immune system

Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of

leukocytes.[34] To be specific, this receptor has been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, and induction of cell migration.[6] Through their inhibition of adenylyl cyclase via their Gi/Goα subunits, CB2 receptor agonists cause a reduction in the intracellular levels of cyclic adenosine monophosphate (cAMP).[35][36] CB2 also signals via Gαs and increases intracellular cAMP in human leukocytes, leading to induction of interleukins 6 and 10.[15] Although the exact role of the cAMP cascade in the regulation of immune responses is currently under debate, laboratories have previously demonstrated that inhibition of adenylyl cyclase by CB2 receptor agonists results in a reduction in the binding of transcription factor CREB (cAMP response element-binding protein) to DNA.[34] This reduction causes changes in the expression of critical immunoregulatory genes[35] and ultimately suppression of immune function.[36]

Later studies examining the effect of synthetic cannabinoid agonist JWH-015 on CB2 receptors revealed that changes in cAMP levels result in the phosphorylation of leukocyte receptor tyrosine kinase at Tyr-505, leading to an inhibition of T cell receptor signaling. Thus, CB2 agonists may also be useful for treatment of inflammation and pain, and are currently being investigated, in particular for forms of pain that do not respond well to conventional treatments, such as neuropathic pain.[37] Consistent with these findings are studies that demonstrate increased CB2 receptor expression in the spinal cord, dorsal root ganglion, and activated microglia in the rodent neuropathic pain model, as well as on human hepatocellular carcinoma tumor samples.[38]

CB2 receptors have also been implicated in the regulation of homing and retention of

IgM. While the mechanism behind this process is not fully understood, the researchers suggested that this process may be due to the activation-dependent decrease in cAMP concentration, leading to reduced transcription of genes regulated by CREB, indirectly increasing TCR signaling and IL-2 production.[6]
Together, these findings demonstrate that the endocannabinoid system may be exploited to enhance immunity to certain pathogens and autoimmune diseases.

Clinical applications

CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as

senile plaques, which disrupt neural functioning.[42]

Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans,[43] ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer. The prevalence of this trend suggests that modulating CB2 receptor activity by either selective CB2 receptor agonists or inverse agonists/antagonists depending on the disease and its progression holds unique therapeutic potential for these pathologies [43]

Modulation of cocaine reward

Researchers investigated the effects of CB2 agonists on cocaine self-administration in mice. Systemic administration of JWH-133 reduced the number of self-infusions of cocaine in mice, as well as reducing locomotor activity and the break point (maximum amount of level presses to obtain cocaine). Local injection of JWH-133 into the nucleus accumbens was found to produce the same effects as systemic administration. Systemic administration of JWH-133 also reduced basal and cocaine-induced elevations of extracellular dopamine in the nucleus accumbens. These findings were mimicked by another, structurally different CB2 agonist, GW-405,833, and were reversed by the administration of a CB2 antagonist, AM-630.[44]

Ligands

Many selective ligands for the CB2 receptor are now available.[45]

Agonists

Partial agonists

Unspecified efficacy agonists

Herbal

Inverse agonists

Binding affinities

CB1 affinity (Ki) Efficacy towards CB1 CB2 affinity (Ki) Efficacy towards CB2 Type References
Anandamide 78 nM Partial agonist 370 nM Partial agonist Endogenous
N-Arachidonoyl dopamine 250 nM Agonist 12000 nM ? Endogenous [48]
2-Arachidonoylglycerol 58.3 nM Full agonist 145 nM Full agonist Endogenous [48]
2-Arachidonyl glyceryl ether 21 nM Full agonist 480 nM Full agonist Endogenous
Tetrahydrocannabinol 10 nM Partial agonist 24 nM Partial agonist Phytogenic [49]
EGCG
 33.6 μM Agonist >50 μM ? Phytogenic [50]
EGC 35.7 μM Agonist >50 μM ? Phytogenic [50]
ECG 47.3 μM Agonist >50 μM ? Phytogenic [50]
N-alkylamide - - <100 nM Partial agonist Phytogenic [51]
β-Caryophyllene - - <200 nM Full agonist Phytogenic [51]
Falcarinol <1 μM Inverse agonist ? ? Phytogenic [51]
Rutamarin - - <10 μM ? Phytogenic [51]
3,3'-Diindolylmethane - - 1 μM Partial Agonist Phytogenic [51]
AM-1221 52.3 nM Agonist 0.28 nM Agonist Synthetic [52]
AM-1235 1.5 nM Agonist 20.4 nM Agonist Synthetic [53]
AM-2232 0.28 nM Agonist 1.48 nM Agonist Synthetic [53]
UR-144 150 nM Full agonist 1.8 nM Full agonist Synthetic [54]
JWH-007 9.0 nM Agonist 2.94 nM Agonist Synthetic [55]
JWH-015 383 nM Agonist 13.8 nM Agonist Synthetic [55]
JWH-018 9.00 ± 5.00 nM Full agonist 2.94 ± 2.65 nM Full agonist Synthetic [55]

Evolution

Paralogues

Source:[56]

References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062585 – Ensembl, May 2017
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External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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