Zac Imiola (Herbalist)
Kava Connoisseur
Can someone like @verticity translate this for us and maybe since yangonin shows CB1 activity we can get a better underanding
this is about cannabinoid receptors not cannabis*
Receptors
The two known cannabinoid receptors, designated type 1 (CB1R) and type 2 (CB2R), are Gi/o protein–coupled, seven-transmembrane domain receptors (GPCRs) with different tissue distributions and functions. The CB1R is the most abundantly expressed GPCR in the central nervous system (CNS) (2, 3), and in the human brain the highest levels of CNR1 (the gene encoding for CB1R) transcription occur in hippocampus, striatum, cortex, and amygdala, with intermediate levels in cerebellum (4, 5). The level of CB1R expression in human cerebellum (3) is lower than in primates and rodents, possibly explaining why catalepsy is one of the tetrad of definitive behaviors seen in rodents exposed to cannabinoids (6) but cannabis-induced catatonia is rarely observed in humans (7) (Supplemental Figure 1a). In contrast, CB2R expression is generally low in the CNS, where it is restricted mostly to microglia, but is high in peripheral immune cells and tissues (8). Microglial CB2R expression increases dramatically following neuropathic injury or inflammatory encephalomyelitis (9), which is why CB2R is an attractive pain management and immune modulatory target, particularly because CB2R agonists do not induce THC-like psychoactivity (2). Even so, there is some evidence of CB2R expression in the rodent brain (10), although a consensus on whether CB2R is expressed at a significant functional level has not yet been achieved. However, several groups have produced data demonstrating CB2R in different neural tissues and have shown CB2R knockout animals demonstrate not only altered electrophysiological responses (10a) but also behavioral memory deficits (10b). Human positron emission tomography (PET) brain imaging studies show negligible, if any, CB2R ligand-specific binding in the brain of healthy individuals, which might reflect the poor sensitivity of these ligands for detecting low levels of CB2R (Supplemental Figure 1b).
The CB1Rs are located primarily on GABAergic and glutamatergic neuronal presynaptic terminals, where they serve to restrict neurotransmitter release and modulate neuronal firing. This is accomplished by inhibiting the voltage-gated calcium channels that control neurotransmitter release and by activating inwardly rectifying potassium channels that reduce the probability of neuronal firing (2). Upon CB1R activation, the receptors' associated G protein subunits uncouple; these subunits interact with ion channels, thereby modulating protein kinase A (PKA) (by inhibiting cyclic adenosine monophosphate synthesis) and upregulating extracellular signal–regulated kinase (ERK) pathways (11). Whereas ion channel modulation allows ECBs to very rapidly downregulate neuronal circuits, it is the kinases that mediate the long-lasting effects of cannabinoids. One example is the tolerance that develops with chronic cannabis exposure, which is a function of CB1R expression downregulation and is modulated by ERK–β-arrestin interactions (12). CB1R expression is a dynamic event: Soon after the receptors are activated, they are internalized from the membrane into endosomes. Some of these CB1Rs will return to the membrane, whereas others become destined for proteolysis. The balance between the rate of membrane expression and internalization regulates the number of active receptors on both pre- and postsynaptic membranes (13) (see the sidebar, Synaptic Distribution of Endocannabinoid Agonists). The ERK stimulation that follows CB1R activation plays a role in tuning this overall system, which controls CB1R levels during periods of both high CB1R activation and high synaptic activity (12). Receptor internalization is driven by the binding of β-arrestin to CB1R as soon as the G proteins disassociate, but the affinity of the interaction between the receptor and β-arrestin determines whether it will be returned to the membrane or broken down (14). Different CB1R agonists induce varying levels of engagement between the receptor and β-arrestin and therefore are more or less powerful inducers of CB1R downregulation and tolerance (14). However, the degree to which an agonist induces a tight bond with β-arrestin may not be related to its relative efficacy at inducing other CB1R-related downstream signals. For example, THC is not as efficacious as AEA or 2-AG at activating PKA or ERK pathways (15), but it is significantly more effective at promoting β-arrestin association, receptor internalization, and ultimately tolerance to its effects (16).
this is about cannabinoid receptors not cannabis*
Receptors
The two known cannabinoid receptors, designated type 1 (CB1R) and type 2 (CB2R), are Gi/o protein–coupled, seven-transmembrane domain receptors (GPCRs) with different tissue distributions and functions. The CB1R is the most abundantly expressed GPCR in the central nervous system (CNS) (2, 3), and in the human brain the highest levels of CNR1 (the gene encoding for CB1R) transcription occur in hippocampus, striatum, cortex, and amygdala, with intermediate levels in cerebellum (4, 5). The level of CB1R expression in human cerebellum (3) is lower than in primates and rodents, possibly explaining why catalepsy is one of the tetrad of definitive behaviors seen in rodents exposed to cannabinoids (6) but cannabis-induced catatonia is rarely observed in humans (7) (Supplemental Figure 1a). In contrast, CB2R expression is generally low in the CNS, where it is restricted mostly to microglia, but is high in peripheral immune cells and tissues (8). Microglial CB2R expression increases dramatically following neuropathic injury or inflammatory encephalomyelitis (9), which is why CB2R is an attractive pain management and immune modulatory target, particularly because CB2R agonists do not induce THC-like psychoactivity (2). Even so, there is some evidence of CB2R expression in the rodent brain (10), although a consensus on whether CB2R is expressed at a significant functional level has not yet been achieved. However, several groups have produced data demonstrating CB2R in different neural tissues and have shown CB2R knockout animals demonstrate not only altered electrophysiological responses (10a) but also behavioral memory deficits (10b). Human positron emission tomography (PET) brain imaging studies show negligible, if any, CB2R ligand-specific binding in the brain of healthy individuals, which might reflect the poor sensitivity of these ligands for detecting low levels of CB2R (Supplemental Figure 1b).
The CB1Rs are located primarily on GABAergic and glutamatergic neuronal presynaptic terminals, where they serve to restrict neurotransmitter release and modulate neuronal firing. This is accomplished by inhibiting the voltage-gated calcium channels that control neurotransmitter release and by activating inwardly rectifying potassium channels that reduce the probability of neuronal firing (2). Upon CB1R activation, the receptors' associated G protein subunits uncouple; these subunits interact with ion channels, thereby modulating protein kinase A (PKA) (by inhibiting cyclic adenosine monophosphate synthesis) and upregulating extracellular signal–regulated kinase (ERK) pathways (11). Whereas ion channel modulation allows ECBs to very rapidly downregulate neuronal circuits, it is the kinases that mediate the long-lasting effects of cannabinoids. One example is the tolerance that develops with chronic cannabis exposure, which is a function of CB1R expression downregulation and is modulated by ERK–β-arrestin interactions (12). CB1R expression is a dynamic event: Soon after the receptors are activated, they are internalized from the membrane into endosomes. Some of these CB1Rs will return to the membrane, whereas others become destined for proteolysis. The balance between the rate of membrane expression and internalization regulates the number of active receptors on both pre- and postsynaptic membranes (13) (see the sidebar, Synaptic Distribution of Endocannabinoid Agonists). The ERK stimulation that follows CB1R activation plays a role in tuning this overall system, which controls CB1R levels during periods of both high CB1R activation and high synaptic activity (12). Receptor internalization is driven by the binding of β-arrestin to CB1R as soon as the G proteins disassociate, but the affinity of the interaction between the receptor and β-arrestin determines whether it will be returned to the membrane or broken down (14). Different CB1R agonists induce varying levels of engagement between the receptor and β-arrestin and therefore are more or less powerful inducers of CB1R downregulation and tolerance (14). However, the degree to which an agonist induces a tight bond with β-arrestin may not be related to its relative efficacy at inducing other CB1R-related downstream signals. For example, THC is not as efficacious as AEA or 2-AG at activating PKA or ERK pathways (15), but it is significantly more effective at promoting β-arrestin association, receptor internalization, and ultimately tolerance to its effects (16).
