Cannabinoid receptor 1 (CB1), is aG protein-coupledcannabinoid receptor that in humans is encoded by theCNR1gene.[5] It was discovered by determination and characterization in 1988,[6] andcloned in 1990 for the first time.[7][8][9] The human CB1 receptor isexpressed in theperipheral nervous system andcentral nervous system.[5] It is activated by endogenous cannabinoids[10] calledendocannabinoids, a group ofretrograde neurotransmitters that include lipids, such asanandamide and2-arachidonoylglycerol; plantphytocannabinoids, such asdocosatetraenoylethanolamide found inwild dagga, the compoundtetrahydrocannabinol which is an active constituent of thepsychoactive drugcannabis; andsynthetic analogs of tetrahydrocannabinol. CB1 isantagonized by the phytocannabinoidtetrahydrocannabivarin at low doses and at higher doses, it activates the CB1 receptor as anagonist, but with less potency than tetrahydrocannabinol.[11][12][13]
The primaryendogenous agonist of the human CB1 receptor isanandamide.[5]
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.[14][15] The receptor may exist as ahomodimer or formheterodimers or otherGPCR oligomers with differentclasses of G-protein-coupled receptors. Observed heterodimers includeA2A–CB1, CB1–D2,OX1–CB1,μOR–CB1, while many more may only be stable enough to exist in vivo.[16][17] The CB1 receptor possesses anallosteric modulatorybinding site.[18]
The CB1 receptor is encoded by the geneCNR1,[19] located on human chromosome 6.[20] Two transcript variants encoding different isoforms have been described for this gene.[19] CNR1orthologs[21] have been identified in mostmammals.
The CNR1 gene has a structure consisting of a single coding-exon and multiple alternative 5' untranslated exons. The CB1 receptor is created bytranscription of the last exon on the CNR1 gene.[22]
The CB1 receptor is a pre-synapticheteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective andpertussis toxin-sensitive manner.[19] The CB1 receptor is activated bycannabinoids, generated naturally inside the body (endocannabinoids) or exogenously, normally throughcannabis or a relatedsynthetic 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 ofGi, which decreases intracellular cAMP concentration by inhibiting its productionenzyme,adenylate cyclase, and increasesmitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB1 receptor activation may be coupled toGs proteins, which stimulateadenylate cyclase.[17] cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influencedinwardly rectifying potassium channels (=Kir or IRK),[23] andcalcium channels, which are activated by cAMP-dependent interaction with such molecules asprotein kinase A (PKA),protein kinase C (PKC),Raf-1,ERK,JNK,p38,c-fos,c-jun, and others.[24]
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.[20] 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 beallosterically modulated by synthetic ligands[25] in a positive[26] and negative[27] manner.In vivo exposure to tetrahydrocannabinol impairslong-term potentiation and leads to a reduction of phosphorylatedCREB.[28]
The signaling properties of activated CB1 are furthermore modified by the presence ofSGIP1, that hinders receptor internalization and decreasesERK1/2 signalling while augmenting the interaction withGRK3,β-arrestin-2.[29][30]
In summary, CB1 receptor activity has been found to be coupled to certain ion channels, in the following manner:[17]
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.[22] 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.[31] 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.[22] Repeated administration of receptor agonists may result in receptor internalization and/or a reduction in receptor protein signaling.[17]
Theinverse agonistMK-9470 makes it possible to producein vivo images of the distribution of CB1 receptors in the human brain withpositron emission tomography.[32]
The CB1 receptor is recognized as the most abundantmetabotropic receptor in the brain.[10] CB1 receptors are found moderately to highly expressed within thecerebral cortex (cingulate gyrus,prefrontal cortex, andhippocampus),periaqueductal gray,hypothalamus,amygdala,cerebellum, andbasal ganglia (globus pallidus,substantia nigra).[31] Varying levels of CB1 can also be detected in theolfactory bulb,cortical regions (neocortex,pyriform cortex), parts ofbasal ganglia,thalamic,hypothalamic, andbrainstem nuclei, as well as in subcortical regions (e.g., theseptal region), andcerebellar cortex.[24]
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-termplasticity in which the depolarization of a single neuron induces a reduction inGABA-mediated inhibition, in effect exciting the postsynaptic cell.[20]
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.[31]
CB1mRNA transcripts are abundant inGABAergic interneurons of thehippocampus, indirectly reflecting the expression of these receptors and elucidating the established effect of cannabinoids onmemory. These receptors are densely located incornu ammonis pyramidal cells, which are known to releaseglutamate. Cannabinoids suppress the induction ofLTP andLTD in the hippocampus by inhibiting these glutamatergic neurons. By reducing the concentration of glutamate released below the threshold necessary to depolarize the postsynapticNMDA receptor,[20] 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.[33] 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 ofacetylcholine. 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 ofmyelin formation, and thus the individual segregation of axons.
CB1 receptors are expressed throughout thebasal ganglia and have well-established effects on movement inrodents. As in thehippocampus, these receptors inhibit the release ofglutamate orGABA 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 appliedcannabinoids, whereas an enhancement of movement may occur upon moderate dosages.[20] 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.
The role of the CB1 receptor in the regulation of motor movements is complicated by the additional expression of this receptor in thecerebellum andneocortex, two regions associated with the coordination and initiation of movement. Research suggests that anandamide is synthesized byPurkinje cells and acts on presynaptic receptors to inhibit glutamate release from granule cells orGABA 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.[20] 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.[33]
Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB1 receptors onspinal cord interneurons in the superficial levels of thedorsal 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 theperiaqueductal 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.[20]
CB1 is expressed on several types of cells inpituitary gland,thyroid gland, and possibly in theadrenal gland.[24] CB1 is also expressed in several cells relating to metabolism, such asfat cells,muscle cells,liver cells (and also in theendothelial cells,Kupffer cells andstellate cells of theliver), and in thedigestive tract.[24] It is also expressed in thelungs and thekidney.
CB1 is present onLeydig cells and humansperms. Infemales, it is present in theovaries,oviductsmyometrium,decidua, andplacenta. It has also been implicated in the proper development of theembryo.[24]
CB1 is also expressed in theretina. In the retina, they are expressed in the photoreceptors, inner plexiform, outer plexiform, bipolar cells, ganglion cells, and retinal pigment epithelium cells.[34] 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.[35]
The activation of CB1 in the human body generally inhibits neurotransmitter release, controls pain, regulates metabolism, and monitors thecardiovascular system.[36] CB1 receptors are implicated in a number of physiological processes related to thecentral nervous system (CNS) including brain development, learning and memory, motor behavior, regulation of appetite, body temperature, pain perception, and inflammation.[10]
The localization of CB1 receptors is expressed in several neuronal types, includingGABAergic,glutamatergic, andserotonergic neurons. CB1 receptors localized in GABAergic neurons can modulate food intake, learning and memory processes, drug addiction, and 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.[10]
Clinically, CB1 is a direct drug target foraddiction, pain,epilepsy, andobesity.[36] CB1 receptor function is involved with severalpsychiatric,neurological,neurodevelopmental, andneurodegenerative disorders includingHuntington's disease (HD),multiple sclerosis (MS), andAlzheimer'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 againstamyloid-β (Aβ) toxicity in AD.[37] In several brain regions, including thedorsolateral prefrontal cortex (DLPFC) andhippocampus, dysregulation of the CB1 receptor is implicated in the development ofschizophrenia. Abnormal functioning of the CB1 receptor compromises intricate neural systems that are responsible for controlling cognition and memory, which contributes to the pathology.[22]PET imaging modalities implicate that alterations of CB1 levels in certain brain systems are strongly associated with schizophrenia symptoms.Neurobehavioral disorders, such asattention deficit hyperactivity disorder (ADHD), are associated with genetic variants of CNR1 in rat models of ADHD.[31]
Selective CB1 agonists may be used to isolate the effects of the receptor from the CB2 receptor, as most cannabinoids and endocannabinoids bind to both receptor types.[20]CB1 selective antagonists such asrimonabant are used for weight reduction andsmoking cessation. A substantial number of antagonists of the CB1 receptor have been discovered and characterized.TM38837 has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.
| 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 | [41] |
| 2-Arachidonoylglycerol | 58.3 nM | Full agonist | 145 nM | Full agonist | Endogenous | [41] |
| 2-Arachidonyl glyceryl ether | 21 nM | Full agonist | 480 nM | Full agonist | Endogenous | |
| Tetrahydrocannabinol | 10 nM | Partial agonist | 24 nM | Partial agonist | Phytogenic | [42] |
| EGCG | 33600 nM | Agonist | 50000+ nM | ? | Phytogenic | |
| AM-1221 | 52.3 nM | Agonist | 0.28 nM | Agonist | Synthetic | [43] |
| AM-1235 | 1.5 nM | Agonist | 20.4 nM | Agonist | Synthetic | [44] |
| AM-2232 | 0.28 nM | Agonist | 1.48 nM | Agonist | Synthetic | [44] |
| UR-144 | 150 nM | Full agonist | 1.8 nM | Full agonist | Synthetic | [45] |
| JWH-007 | 9.0 nM | Agonist | 2.94 nM | Agonist | Synthetic | [46] |
| JWH-015 | 383 nM | Agonist | 13.8 nM | Agonist | Synthetic | [46] |
| JWH-018 | 9.00 ± 5.00 nM | Full agonist | 2.94 ± 2.65 nM | Full agonist | Synthetic | [47] |
TheCNR1 gene is used in animals as anuclear DNA phylogenetic marker.[21] This intronless gene has first been used to explore the phylogeny of the major groups ofmammals,[48] and contributed to reveal thatplacental orders are distributed into five major clades:Xenarthra,Afrotheria,Laurasiatheria,Euarchonta, andGlires. CNR1 has also proven useful at lowertaxonomic levels, such asrodents,[49][50] and for the identification ofdermopterans as the closest primate relatives.[51]
Source:[52]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
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