Cannabinoid receptor 1
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Cannabinoid receptor 1 (CB1), is a
The primary endogenous agonist of the human CB1 receptor is anandamide.[5]
Structure
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.
The CB1 receptor is encoded by the gene CNR1,
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. [17]
Mechanism
The CB1 receptor is a pre-synaptic
compound.Research suggests that the majority of CB1 receptors are coupled through Gi/o proteins. Upon activation, CB1 receptor exhibits its effects mainly through activation of
In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB1 receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release.[15] The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type.
The CB1 receptor can also be
The signaling properties of activated CB1 are furthermore modified by the presence of SGIP1, that hinders receptor internalization and decreases ERK1/2 signalling while augmenting the interaction with GRK3, β-arrestin-2.[24][25]
In summary, CB1 receptor activity has been found to be coupled to certain ion channels, in the following manner:[12]
- Positively to inwardly rectifying and A-type outward potassium channels.
- Negatively to D-type outward potassium channels
- Negatively to N-type and P/Q-type calcium channels.
Expression
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.[17] 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.[26] 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.[17] Repeated administration of receptor agonists may result in receptor internalization and/or a reduction in receptor protein signaling.[12]
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.[27]
Brain
The CB1 receptor is recognized as the most abundant
CB1 receptors are expressed most densely in the central nervous system and 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
Brainstem
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.[26]
Hippocampal formation
CB1
Basal ganglia
CB1 receptors are expressed throughout the
Cerebellum and neocortex
The role of the CB1 receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the
Spine
Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB1 receptors on
Other
CB1 is expressed on several types of cells in
CB1 is present on
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.[29] 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.[30]
Physiological and pathological conditions
The activation of CB1 in the human body generally promotes neurotransmitter release, controls pain, regulates metabolism, and monitors the cardiovascular system.[31] 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.[6]
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.[6]
Clinically, CB1 is a direct drug target for addiction, pain, epilepsy, and obesity.[31] 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.[32] 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.[17] 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.[26]
Use of antagonists
Selective CB1 agonists may be used to isolate the effects of the receptor from the CB1 receptor, as most cannabinoids and endocannabinoids bind to both receptor types.[15]
Ligands
Agonists
Selective
Unspecified efficacy
Partial
Endogenous
Phyto
Full
Endogenous
Synthetic
Allosteric agonist
- GAT228[35]
Antagonists
- Cannabigerol
- Ibipinabant
- Otenabant
- Tetrahydrocannabivarin
- Virodhamine (Endogenous CB1 antagonist and CB2 agonist)
Inverse agonists
- Rimonabant
- Taranabant
- Zevaquenabant
- INV-202
Allosteric modulators
- Lipoxin A4 – endogenous, PAM
- ZCZ-011 – PAM
- Pregnenolone – endogenous, NAM
- Cannabidiol – NAM[28]
- Fenofibrate – NAM
- GAT100 – NAM
- PSNCBAM-1 – NAM
- RVD-Hpα – NAM
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 | [36] |
2-Arachidonoylglycerol | 58.3 nM | Full agonist | 145 nM | Full agonist | Endogenous | [36] |
2-Arachidonyl glyceryl ether | 21 nM | Full agonist | 480 nM | Full agonist | Endogenous | |
Tetrahydrocannabinol | 10 nM | Partial agonist | 24 nM | Partial agonist | Phytogenic | [37] |
EGCG
|
33600 nM | Agonist | 50000+ nM | ? | Phytogenic | |
AM-1221 | 52.3 nM | Agonist | 0.28 nM | Agonist | Synthetic | [38] |
AM-1235 | 1.5 nM | Agonist | 20.4 nM | Agonist | Synthetic | [39] |
AM-2232 | 0.28 nM | Agonist | 1.48 nM | Agonist | Synthetic | [39] |
UR-144 | 150 nM | Full agonist | 1.8 nM | Full agonist | Synthetic | [40] |
JWH-007 | 9.0 nM | Agonist | 2.94 nM | Agonist | Synthetic | [41] |
JWH-015 | 383 nM | Agonist | 13.8 nM | Agonist | Synthetic | [41] |
JWH-018 | 9.00 ± 5.00 nM | Full agonist | 2.94 ± 2.65 nM | Full agonist | Synthetic | [42] |
Evolution
The CNR1 gene is used in animals as a
Paralogues
Source:[47]
- CNR2
- S1PR1
- LPAR1
- S1PR3
- S1PR5
- S1PR2
- GPR6
- GPR12
- S1PR4
- LPAR3
- LPAR2
- GPR3
- MC3R
- MC5R
- MC2R
- MC1R
- MC4R
- GPR119
See also
- Discovery and development of Cannabinoid Receptor 1 Antagonists
- Cannabinoid receptor
- Cannabinoid receptor type 2(CB2)
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000118432 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000044288 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c Abood M, Barth F, Bonner TI, Cabral G, Casellas P, Cravatt BF, et al. (22 August 2018). "CB1 Receptor". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 9 November 2018.
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- ^ a b c "Entrez Gene: CNR1 cannabinoid receptor 1 (brain)".
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- ^ a b "OrthoMaM phylogenetic marker: CNR1 coding sequence". Archived from the original on 22 December 2015. Retrieved 23 November 2009.
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- ^ "PDSP Database – UNC". Archived from the original on 8 November 2013. Retrieved 11 June 2013.
- ^ WO patent 200128557, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2001-06-07
- ^ a b US patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10
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- ^ "CNR1 paralogs". GeneCards®: The Human Gene Database.
External links
- "Cannabinoid Receptors: CB1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 5 March 2012.
- Cannabinoid receptor 1 (CNR1) Human Protein Atlas
This article incorporates text from the United States National Library of Medicine, which is in the public domain.