Cannabinoid receptor type 2

The cannabinoid receptor type 2, abbreviated as CB2, is a is_associated_with::G protein-coupled receptor from the is_associated_with::cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the is_associated_with::cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of is_associated_with::tetrahydrocannabinol, the active agent in is_associated_with::marijuana, and other is_associated_with::phytocannabinoids (natural cannabinoids). The principal endogenous ligand for the CB2 receptor is is_associated_with::2-arachidonoylglycerol (2-AG).

CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor that could explain the pharmacological properties of is_associated_with::tetrahydrocannabinol. The receptor was identified among is_associated_with::cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor type 1 (CB1) receptor, discovered in 1990. 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. Approximately 360 is_associated_with::amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor.

As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains, a glycosylated is_associated_with::N-terminus, and an intracellular is_associated_with::C-terminus. The C-terminus of CB2 receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and is_associated_with::downregulation following repeated agonist application, perhaps causing the receptor to become less responsive to particular ligands.

The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity. When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%. The amino acid sequence of the CB2 receptor is less highly conserved across human and rodent species as compared to the amino acid sequence of the CB1 receptor. Based on computer modeling, ligand interactions with CB2 receptor residues S3.31 and F5.46 appears to determine differences between CB1 and CB2 receptor selectivity. In CB2 receptors, is_associated_with::lipophilic groups interact with the F5.46 residue, allowing them to form a is_associated_with::hydrogen bond with the S3.31 residue. These interactions induce a is_associated_with::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.

Mechanism
Like the CB1 receptors, CB2 receptors inhibit the activity of is_associated_with::adenylyl cyclase through their Gi/Goα subunits. Through their Gβγ subunits, CB2 receptors are also known to be coupled to the is_associated_with::MAPK-ERK pathway, a complex and highly conserved is_associated_with::signal transduction pathway, which critically regulates a number of important cellular processes in both mature and developing tissues. Activation of the MAPK-ERK pathway by CB2 receptor is_associated_with::agonists acting through the Gβγ subunit ultimately results in changes in is_associated_with::cell migration as well as in an induction of the growth-related gene is_associated_with::Zif268 (also known as Krox-24, NGFI-A, and egr-1). The Zifi268 gene encodes a transcriptional regulator implicated in is_associated_with::neuroplasticity and is_associated_with::long term memory formation.

At present, there are five recognized is_associated_with::cannabinoids produced endogenously throughout the body: is_associated_with::Arachidonoylethanolamine (anandamide), is_associated_with::2-arachidonoyl glycerol (2-AG), is_associated_with::2-arachidonyl glyceryl ether (noladin ether), is_associated_with::virodhamine, as well as the recently discovered is_associated_with::N-arachidonoyl-dopamine (NADA). Many of these ligands appear to exhibit properties of is_associated_with::functional selectivity at the CB2 receptor: 2-AG preferentially activates the MAPK-ERK pathway, while noladin preferentially inhibits adenylyl cyclase. Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB2 receptors. Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors.

Immune System
Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the is_associated_with::immune system and found CB2 receptor is_associated_with::mRNA is found throughout tissues of the is_associated_with::spleen, is_associated_with::tonsils, and is_associated_with::thymus gland. is_associated_with::Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues, where they are primarily responsible for mediating is_associated_with::cytokine release. These receptors were primarily localized on immune cells such as is_associated_with::monocytes, is_associated_with::macrophages, is_associated_with::B-cells, and is_associated_with::T-cells.

Brain
Further investigation into the expression patterns of the CB2 receptors revealed that CB2 receptor gene transcripts are also expressed in the is_associated_with::brain, though not as densely as the CB1 receptor and located on different cells. Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on is_associated_with::microglia, but not is_associated_with::neurons.

Gastrointestinal System
CB2 receptors are also found throughout the is_associated_with::gastrointestinal system, where they modulate intestinal inflammatory response. Thus, CB2 receptor is a potential therapeutic target for is_associated_with::inflammatory bowel diseases, such as is_associated_with::Crohn's disease and is_associated_with::ulcerative colitis. 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. Cannabinoid receptor agonists reduce gut motility in IBS patients.

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 is_associated_with::mast cells, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli.

Immune System
Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of is_associated_with::leukocytes. 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. Through their inhibition of adenylyl cyclase via their Gi/Goα subunits, CB2 receptor agonists cause a reduction in the intracellular levels of is_associated_with::cyclic adenosine monophosphate (cAMP). 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 is_associated_with::transcription factor is_associated_with::CREB (cAMP response element-binding protein) to is_associated_with::DNA. This reduction causes changes in the expression of critical immunoregulatory genes and ultimately suppression of immune function.

Later studies examining the effect of synthetic cannabinoid agonist is_associated_with::JWH-015 on CB2 receptors revealed that changes in cAMP levels result in the phosphorylation of is_associated_with::leukocyte receptor tyrosine kinase at Tyr-505, leading to an inhibition of is_associated_with::T cell receptor signaling. Thus, CB2 agonists may also be useful for treatment of is_associated_with::inflammation and pain, and are currently being investigated, in particular for forms of pain that do not respond well to conventional treatments, such as is_associated_with::neuropathic pain. 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 heptocellular carcinoma tumor samples.

CB2 receptors have also been implicated in the regulation of homing and retention of is_associated_with::marginal zone is_associated_with::B cells. A study using knock-out mice found that CB2 receptor is essential for the maintenance of both MZ B cells and their precursor is_associated_with::T2-MZP, though not their development. Both B cells and their precursors lacking this receptor were found in reduced numbers, explained by the secondary finding that 2-AG signaling was demonstrated to induce proper B cell migration to the MZ. Without the receptor, there was an undesirable spike in the blood concentration of MZ B lineage cells and a significant reduction in the production of is_associated_with::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 is_associated_with::CREB, indirectly increasing TCR signaling and IL-2 production. Together, these findings demonstrate that the endocannabinoid system maybe 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 is_associated_with::Alzheimer's disease. Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native is_associated_with::beta-amyloid protein from frozen human tissues. In patient's with Alzheimer's disease, beta-amyloid proteins form aggregates known as is_associated_with::senile plaques, which disrupt neural functioning.

Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, 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

Modulation of cocaine reward
Researchers investigated the effects of CB2 agonists on is_associated_with::cocaine self-administration in mice. Systemic administration of is_associated_with::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 is_associated_with::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 is_associated_with::dopamine in the nucleus accumbens. These findings were mimicked by another, structurally different CB2 agonist, is_associated_with::GW-405,833, and were reversed by the administration of a CB2 antagonist, is_associated_with::AM-630.

Ligands
Many selective ligands for the CB2 receptor are now available.

Partial agonists

 * is_associated_with::GW-405,833

Unspecified efficacy agonists

 * is_associated_with::AM-1241
 * is_associated_with::HU-308
 * is_associated_with::JWH-015
 * is_associated_with::JWH-133
 * is_associated_with::L-759,633
 * is_associated_with::L-759,656

Herbal

 * is_associated_with::Echinacea purpurea

Inverse agonists

 * is_associated_with::AM-630
 * is_associated_with::BML-190
 * is_associated_with::JTE-907
 * is_associated_with::SR-144,528