User:Sdavis81/Cannabinoid receptor type 1
Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene.[1] The human CB1 receptor is expressed in the peripheral nervous system and central nervous system.[1]It is activated by endogenous cannabinoids[2] called endocannabinoids, a group of retrograde neurotransmitters that include lipids, such as anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).[3][4]
The primary endogenous agonist of the human CB1 receptor is anandamide.[1]
Structure
[edit]The CB1 receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail.[5][6] The receptor may exist as a homodimer or form heterodimers or other GPCR oligomers with different classes of G-protein-coupled receptors. Observed heterodimers include A2A–CB1, CB1–D2, OX1–CB1, μOR–CB1, while many more may only be stable enough to exist in vivo.[7][8] The CB1 receptor possesses an allosteric modulatory binding site.[9]
The CB1 receptor is encoded by the gene CNR1,[10] located on human chromosome 6.[11] Two transcript variants encoding different isoforms have been described for this gene.[10] CNR1 orthologs[12] have been identified in most mammals.
The CNR1 gene has a structure consisting of a single coding-exon and multiple alternative 5' untranslated exons. The CB1 receptor is created by transcription of the last exon on the CNR1 gene. [13]
Expression
[edit]CB1 receptors are localized throughout the central and peripheral nervous systems, particularly on axon terminals in the cerebellum, hippocampus, basal ganglia, frontal cortex, amygdala, hypothalamus, and midbrain.[13] The CB1 receptor is primarily expressed in the presynaptic terminals of GABAergic (amygdala and cerebellum), glutamatergic (cortex, hippocampus and amygdala), dopaminergic, GABAergic interneurons, cholinergic neurons, noradrenergic, and serotonergic neurons.[14] Acting as a neuromodulator, the CB1 receptor inhibits the release of both excitatory and inhibitory neurotransmitters including acetylcholine, glutamate, GABA, noradrenaline, 5-HT, dopamine, D-aspartate, and cholecystokinin.[13] The CB1 receptor is expressed pre-synaptically at both glutaminergic and GABAergic interneurons and, in effect, acts as a neuromodulator to inhibit release of glutamate and GABA.[11] Repeated administration of receptor agonists may result in receptor internalization and/or a reduction in receptor protein signalling.[15]
The inverse agonist MK-9470 makes it possible to produce in vivo images of the distribution of CB1 receptors in the human brain with positron emission tomography.[16]
Brain
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/1/1b/CNR1%2C_ISH%2C_mouse.jpg/220px-CNR1%2C_ISH%2C_mouse.jpg)
The CB1 receptor is recognized as the most abundant metabotropic receptor in the brain.[2] CB1 receptors are found moderately to highly expressed within the cerebral cortex (cingulate gyrus, prefrontal cortex, and hippocampus), periaqueductal gray, hypothalamus, amygdala, cerebellum, and basal ganglia (globus pallidus, substantia nigra).[14] Varying levels of CB1 expression can also be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic, hypothalamic, and brainstem nuclei, and other as well as in subcortical regions (e.g., the septal region), and cerebellar cortex., and brainstem nuclei (e.g., the periaqueductal gray).[17]
CB1 receptors are largely responsible for mediating the effects of cannabinoid binding in the brain. Endocannabinoids released by a depolarized neuron bind to CB1 receptors on pre-synaptic glutamatergic and GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. Limiting glutamate release causes reduced excitation, while limiting GABA release suppresses inhibition, a common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated inhibition, in effect exciting the postsynaptic cell.[11]
Brainstem
[edit]High expression of CB1 is found in brainstem medullary nuclei, including the nucleus of the solitary tract and area postrema. CB1 receptor is relatively low in medullary respiratory brainstem control centers.[14]
Hippocampal formation
[edit]CB1 mRNA transcripts are abundant in GABAergic interneurons of the hippocampus, indirectly reflecting the expression of these receptors and elucidating the established effect of cannabinoids on memory. These receptors are densely located in cornu ammonis pyramidal cells, which are known to release glutamate. Cannabinoids suppress the induction of LTP and LTD in the hippocampus by inhibiting these glutamatergic neurons. By reducing the concentration of glutamate released below the threshold necessary to depolarize the postsynaptic receptor NMDA,[18] a receptor known to be directly related to the induction of LTP and LTD, cannabinoids are a crucial factor in the selectivity of memory. These receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. However, a higher density is found within GABAergic cells.[19] This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, net hippocampal activity is raised. In addition, CB1 receptors in the hippocampus indirectly inhibit the release of acetylcholine. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release. Cannabinoids also likely play an important role in the development of memory through their neonatal promotion of myelin formation, and thus the individual segregation of axons.
Basal ganglia
[edit]CB1 receptors are expressed throughout the basal ganglia and have well-established effects on movement in rodents. As in the hippocampus, these receptors inhibit the release of glutamate or GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Consistent with the variable expression of both excitatory glutamate and inhibitory GABA interneurons in both the basal ganglia's direct and indirect motor loops, synthetic cannabinoids are known to influence this system in a dose-dependent triphasic pattern. Decreased locomotor activity is seen at both higher and lower concentrations of applied cannabinoids, whereas an enhancement of movement may occur upon moderate dosages.[18] However, these dose-dependent effects have been studied predominately in rodents, and the physiological basis for this triphasic pattern warrants future research in humans. Effects may vary based on the site of cannabinoid application, input from higher cortical centers, and whether drug application is unilateral or bilateral.
Cerebellum and neocortex
[edit]The role of the CB1 receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the cerebellum and neocortex, two regions associated with the coordination and initiation of movement. Research suggests that anandamide is synthesized by Purkinje cells and acts on presynaptic receptors to inhibit glutamate release from granule cells or GABA release from the terminals of basket cells. In the neocortex, these receptors are concentrated on local interneurons in cerebral layers II-III and V-VI.[18] Compared to rat brains, humans express more CB1 receptors in the cerebral cortex and amygdala and less in the cerebellum, which may help explain why motor function seems to be more compromised in rats than humans upon cannabinoid application.[19]
Spine
[edit]Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB1 receptors on spinal cord interneurons in the superficial levels of the dorsal horn, known for its role in nociceptive processing. In particular, the CB1 is heavily expressed in layers 1 and 2 of the spinal cord dorsal horn and in lamina 10 by the central canal. Dorsal root ganglion also express these receptors, which target a variety of peripheral terminals involved in nociception. Signals on this track are also transmitted to the periaqueductal gray (PAG) of the midbrain. Endogenous cannabinoids are believed to exhibit an analgesic effect on these receptors by limiting both GABA and glutamate of PAG cells that relate to nociceptive input processing, a hypothesis consistent with the finding that anandamide release in the PAG is increased in response to pain-triggering stimuli.[18]
Other
[edit]CB1 is expressed on several types of cells in pituitary gland, thyroid gland, and possibly in the adrenal gland.[20] CB1 is also expressed in several cells relating to metabolism, such as fat cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tract.[20] It is also expressed in the lungs and the kidney.
CB1 is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua, and placenta. It has also been implicated in the proper development of the embryo.[20]
CB1 is also expressed in the retina. In the retina, they are expressed in the photoreceptors, inner plexiform, outer plexiform, bipolar cells, ganglion cells, and retinal pigment epithelium cells.[21] In the visual system, cannabinoids agonist induce a dose dependent modulation of calcium, chloride and potassium channels. This alters vertical transmission between photoreceptor, bipolar and ganglion cells. Altering vertical transmission in turn results in the way vision is perceived.[22]
Physiological and pathological conditions
[edit]The activation of CB1 in the human body generally promotes neurotransmitter release, controls pain, regulates metabolism, and monitors the cardiovascular system.[23] CB1 receptors are implicated in a number of physiological processes related to the central nervous system (CNS) including brain development, learning and memory, motor behavior, regulation of appetite, body temperature, pain perception, and inflammation.[2]
The localization of CB1 receptors is expressed in several neuronal types, including GABAergic, glutamatergic, and serotonergic neurons. CB1 receptors localized in GABAergic neurons can modulate food intake, learning and memory processes, drug addiction, and running related behaviors. CB1 receptors localized in glutamatergic neurons are capable of mediating olfactory processes, neuroprotection, social behaviors, anxiety, and fear memories. The localization of CB1 receptors in serotonergic neurons can regulate emotional responses.[2]
Clinically, CB1 is a direct drug target for addiction, pain, epilepsy, and obesity.[23] CB1 receptor function is involved with several psychiatric, neurological, neurodevelopmental, and neurodegenerative disorders including Huntington's disease (HD), multiple sclerosis (MS), and Alzheimer's disease (AD). Major loss of CB1 receptors is reported in patients with HD. However, stimulation of the CB1 receptor has potential to reduce the progression of HD. Improvements from use of CB agonist in MS are associated with the activation of CB1 and CB2 receptors, leading to dual anti-inflammatory and neuroprotective effects throughout the CNS. Similarly, activation of CB1 and CB2 receptors could provide neuroprotective effects against amyloid-β (Aβ) toxicity in AD.[24] In several brain regions, including the dorsolateral prefrontal cortex (DLPFC) and hippocampus, dysregulation of the CB1 receptor is implicated in the development of schizophrenia. Abnormal functioning of the CB1 receptor compromises intricate neural systems that are responsible for controlling cognition and memory, which contributes to the pathology.[13] PET imaging modalities implicate that alterations of CB1 levels in certain brain systems are strongly associated with schizophrenia symptoms. Neurobehavioral disorders, such as attention deficit hyperactivity disorder (ADHD), are associated with genetic variants of CNR1 in rat models of ADHD.[14]
References
[edit]- ^ a b c Abood M, Barth F, Bonner TI, Cabral G, Casellas P, Cravatt BF, Devane WA, Elphick MR, Felder CC, Herkenham M, Howlett AC, Kunos G, Mackie K, Mechoulam R, Pertwee RG (22 August 2018). "CB1 Receptor". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 9 November 2018.
- ^ a b c d Busquets Garcia, Arnau; Soria-Gomez, Edgar; Bellocchio, Luigi; Marsicano, Giovanni (2016-05-24). "Cannabinoid receptor type-1: breaking the dogmas". F1000Research. 5: 990. doi:10.12688/f1000research.8245.1. ISSN 2046-1402. PMC 4879932. PMID 27239293 – via PubMed Central.
{{cite journal}}
: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, Pertwee RG (December 2005). "Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist". British Journal of Pharmacology. 146 (7): 917–926. doi:10.1038/sj.bjp.0706414. PMC 1751228. PMID 16205722.
- ^ Pertwee RG, Thomas A, Stevenson LA, Ross RA, Varvel SA, Lichtman AH, et al. (March 2007). "The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo". British Journal of Pharmacology. 150 (5): 586–594. doi:10.1038/sj.bjp.0707124. PMC 2189766. PMID 17245367.
- ^ Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM (December 2016). "High-resolution crystal structure of the human CB1 cannabinoid receptor". Nature. 540 (7634): 602–606. Bibcode:2016Natur.540..602S. doi:10.1038/nature20613. PMC 5433929. PMID 27851727.
- ^ Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. (October 2016). "Crystal Structure of the Human Cannabinoid Receptor CB1". Cell. 167 (3): 750–762.e14. doi:10.1016/j.cell.2016.10.004. PMC 5322940. PMID 27768894.
- ^ Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, et al. (November 2008). "mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis". Journal of Pharmacological Sciences. 108 (3): 308–319. doi:10.1254/jphs.08244FP. PMID 19008645.
- ^ Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity. 30 (Suppl 1): S13–S18. doi:10.1038/sj.ijo.0803272. PMID 16570099.
- ^ Nguyen T, Li JX, Thomas BF, Wiley JL, Kenakin TP, Zhang Y (May 2017). "Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor". Medicinal Research Reviews. 37 (3): 441–474. doi:10.1002/med.21418. PMC 5397374. PMID 27879006.
- ^ a b "Entrez Gene: CNR1 cannabinoid receptor 1 (brain)".
- ^ a b c Elphick MR, Egertová M (March 2001). "The neurobiology and evolution of cannabinoid signalling". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486.
- ^ "OrthoMaM phylogenetic marker: CNR1 coding sequence". Archived from the original on 22 December 2015. Retrieved 23 November 2009.
- ^ a b c d Tao, Ran; Li, Chao; Jaffe, Andrew E.; Shin, Joo Heon; Deep-Soboslay, Amy; Yamin, Rae’e; Weinberger, Daniel R.; Hyde, Thomas M.; Kleinman, Joel E. (2020-05-19). "Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia". Translational Psychiatry. 10 (1). doi:10.1038/s41398-020-0832-8. ISSN 2158-3188. PMC 7237456. PMID 32433545 – via PubMed.
{{cite journal}}
: CS1 maint: PMC format (link) - ^ a b c d Haspula, Dhanush; Clark, Michelle A. (2020-10-17). "Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases". International Journal of Molecular Sciences. 21 (20): 7693. doi:10.3390/ijms21207693. ISSN 1422-0067. PMC 7590033. PMID 33080916 – via PubMed.
{{cite journal}}
: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity. 30 (Suppl 1): S13–S18. doi:10.1038/sj.ijo.0803272. PMID 16570099.
- ^ Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, et al. (June 2007). "[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor". Proceedings of the National Academy of Sciences of the United States of America. 104 (23): 9800–9805. Bibcode:2007PNAS..104.9800B. doi:10.1073/pnas.0703472104. PMC 1877985. PMID 17535893.
- ^ Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (February 2006). "The emerging role of the endocannabinoid system in endocrine regulation and energy balance". Endocrine Reviews. 27 (1): 73–100. doi:10.1210/er.2005-0009. PMID 16306385.
- ^ a b c d Elphick MR, Egertová M (March 2001). "The neurobiology and evolution of cannabinoid signalling". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486.
- ^ a b Pertwee RG (January 2008). "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin". British Journal of Pharmacology. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291.
- ^ a b c Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (February 2006). "The emerging role of the endocannabinoid system in endocrine regulation and energy balance". Endocrine Reviews. 27 (1): 73–100. doi:10.1210/er.2005-0009. PMID 16306385.
- ^ Porcella A, Maxia C, Gessa GL, Pani L (March 2000). "The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein". The European Journal of Neuroscience. 12 (3): 1123–1127. doi:10.1046/j.1460-9568.2000.01027.x. PMID 10762343. S2CID 34849187.
- ^ Hoon M, Okawa H, Della Santina L, Wong RO (September 2014). "Functional architecture of the retina: development and disease". Progress in Retinal and Eye Research. 42: 44–84. doi:10.1016/j.preteyeres.2014.06.003. PMC 4134977. PMID 24984227.
- ^ a b Huang, Shenming; Xiao, Peng; Sun, Jinpeng (2020-07-21). "Structural basis of signaling of cannabinoids receptors: paving a way for rational drug design in controling mutiple neurological and immune diseases". Signal Transduction and Targeted Therapy. 5 (1). doi:10.1038/s41392-020-00240-5. ISSN 2059-3635. PMC 7374105. PMID 32694501 – via PubMed.
{{cite journal}}
: CS1 maint: PMC format (link) - ^ Kendall, Debra A.; Yudowski, Guillermo A. (2017). "Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease". Frontiers in Cellular Neuroscience. 10. doi:10.3389/fncel.2016.00294. ISSN 1662-5102. PMC 5209363. PMID 28101004.
{{cite journal}}
: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)