Molecular signaling of synthetic cannabinoids: Comparison of CB1 receptor and TRPV1 channel activation

Andersen, Haley K.; Walsh, Kenneth B.

doi:10.1016/j.ejphar.2021.174301

Cited by 10 publications

(9 citation statements)

References 39 publications

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“…This research targets the GIRK1/2 channel and CB1R internalization responses of four structurally distinct cannabinoids: (±)CP55,940, WIN55,212-2, AEA, and Δ 9 -THC. In this study, the synthetic cannabinoids (±)CP55,950 and WIN55,212-2 were more potent and e cacious at stimulating a GIRK1/2 channel response than AEA and Δ 9 -THC, aligning with previous research [25,30]. Speci cally, the trace of (±)CP55,940's GIRK1/2 response signi cantly differed from the other cannabinoids, suggesting different GIRK1/2channel kinetics (Fig.…”

Section: Discussionsupporting

confidence: 87%

Comparing Cb1 Receptor Girk Channel Responses to Receptor Internalization Using a Kinetic Imaging Assay

Andersen,

Vardakas,

Lamothe

et al. 2024

Preprint

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The type 1 cannabinoid receptor (CB1R) mediates neurotransmitter release and synaptic plasticity in the central nervous system. Endogenous, plant-derived, synthetic cannabinoids bind to CB1R, initiating the inhibitory G-protein (Gi) and the β-arrestin signaling pathways. Within the Gi signaling pathway, CB1R activates G protein-gated, inwardly-rectifying potassium (GIRK) channels. The β-arrestin pathway mediates CB1R expression on the cell surface through receptor internalization. Because of their association with analgesia and drug tolerance, GIRK channels and receptor internalization are of interest to the development of pharmaceuticals. This research used immortalized mouse pituitary gland cells transduced with a pH-sensitive, fluorescently-tagged human CB1R (AtT20-SEPCB1) to measure GIRK channel activity and CB1R internalization. Cannabinoid-induced GIRK channel activity is measured by using a fluorescent membrane-potential sensitive dye. We developed a kinetic imaging assay that visualizes and measures CB1R internalization. All cannabinoids stimulated a GIRK channel response with a rank order potency of WIN55,212-2 > (±)CP55,940 > Δ9-THC > AEA. Efficacy was expressed relative to (±)CP55,940 with a rank order efficacy of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. All cannabinoids stimulated CB1R internalization with a rank order potency of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. Internalization efficacy was normalized to (±)CP55,940 with a rank order efficacy of WIN55,212-2 > AEA > (±)CP55,940 > Δ9-THC. (±)CP55,940 was significantly more potent and efficacious than AEA and Δ9-THC at stimulating a GIRK channel response; however, no significant differences between potency and efficacy were observed with CB1R internalization. No significant differences were found when comparing a cannabinoid’s GIRK channel and CB1R internalization response. In conclusion, AtT20-SEPCB1 cells can be used to outline cannabinoid-induced CB1R internalization. While cannabinoids display differential Gi signaling when compared to each other, this does not extend to CB1R internalization, which is mediated by β-arrestins.

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Section: Discussionsupporting

confidence: 87%

Comparing Cb1 Receptor Girk Channel Responses to Receptor Internalization Using a Kinetic Imaging Assay

Andersen,

Vardakas,

Lamothe

et al. 2024

Preprint

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“…Terpenes may share a common effect of mediating hyperpolarization with synthetic cannabinoids, via G-protein gated inward rectifier potassium (GIRK) channel activation [44,45]. A similar mechanism of action was described for the Nociceptin/OFQ inhibition of capsaicin responses in nodose ganglion neurons, which was reversed by the GIRK channel inhibitor Tertiapin [28].…”

Section: Discussionmentioning

confidence: 79%

Terpenes in Cannabis sativa Inhibit Capsaicin Responses in Rat DRG Neurons via Na+/K+ ATPase Activation

Anand,

Sodergren

2023

IJMS

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Terpenes in Cannabis sativa exert analgesic effects, but the mechanisms are uncertain. We examined the effects of 10 terpenes on capsaicin responses in an established model of neuronal hypersensitivity. Adult rat DRG neurons cultured with neurotrophic factors NGF and GDNF were loaded with Fura2AM for calcium imaging, and treated with individual terpenes or vehicle for 5 min, followed by 1 µMol capsaicin. In vehicle treated control experiments, capsaicin elicited immediate and sustained calcium influx. Most neurons treated with terpenes responded to capsaicin after 6–8 min. Few neurons showed immediate capsaicin responses that were transient or normal. The delayed responses were found to be due to calcium released from the endoplasmic reticulum, as they were maintained in calcium/magnesium free media, but not after thapsigargin pre-treatment. Terpene inhibition of calcium influx was reversed after washout of medium, in the absence of terpenes, and in the presence of the Na+/K+ ATPase inhibitor ouabain, but not CB1 or CB2 receptor antagonists. Thus, terpenes inhibit capsaicin evoked calcium influx by Na+/K+ ATPase activation. Immunofluorescence showed TRPV1 co-expression with α1β1 Na+/K+ ATPase in most neurons while others were either TRPV1 or α1β1 Na+/K+ ATPase positive.

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“…Interestingly, there is a molecular connection between CB1R and PPARs that can dictate the ultimate effects of SCs, intense activation of CB1R by SCs can disturb the neuroprotective effects exerted by PPARs and incite intense inflammatory and oxidative stress responses [60]. Although SCs exhibit limited efficacy in opening TRPV1 channels, some SCs such as XLR-11 were shown to induce a significant activation of these channels and promote neuronal uptake of Ca2 + [61].…”

Section: Neurologic and Psychiatric Effectsmentioning

confidence: 99%

The synthetic cannabinoids menace: a review of health risks and toxicity

Alzu’bi,

Almahasneh,

Khasawneh

et al. 2024

Eur J Med Res

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Synthetic cannabinoids (SCs) are chemically classified as psychoactive substances that target the endocannabinoid system in many body organs. SCs can initiate pathophysiological changes in many tissues which can be severe enough to damage the normal functionality of our body systems. The majority of SCs-related side effects are mediated by activating Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R). The activation of these receptors can enkindle many downstream signalling pathways, including oxidative stress, inflammation, and apoptosis that ultimately can produce deleterious changes in many organs. Besides activating the cannabinoid receptors, SCs can act on non-cannabinoid targets, such as the orphan G protein receptors GPR55 and GPR18, the Peroxisome Proliferator-activated Receptors (PPARs), and the Transient receptor potential vanilloid 1 (TRPV1), which are broadly expressed in the brain and the heart and their activation mediates many pharmacological effects of SCs. In this review, we shed light on the multisystem complications found in SCs abusers, particularly discussing their neurologic, cardiovascular, renal, and hepatic effects, as well as highlighting the mechanisms that intermediate SCs-related pharmacological and toxicological consequences to provide comprehensive understanding of their short and long-term systemic effects. Graphical Abstract

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Molecular signaling of synthetic cannabinoids: Comparison of CB1 receptor and TRPV1 channel activation

Cited by 10 publications

References 39 publications

Comparing Cb1 Receptor Girk Channel Responses to Receptor Internalization Using a Kinetic Imaging Assay

Comparing Cb1 Receptor Girk Channel Responses to Receptor Internalization Using a Kinetic Imaging Assay

Terpenes in Cannabis sativa Inhibit Capsaicin Responses in Rat DRG Neurons via Na+/K+ ATPase Activation

The synthetic cannabinoids menace: a review of health risks and toxicity

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