Cholesterol regulates cannabinoid analgesia through glycine receptors

Yao, Lei; Liu, Chengyuan; Wang, Ning; Du, Feng; Fan, Sijia; Guo, Yujun; Zhang, Li; Pan, Yang; Xiong, Wei

doi:10.1016/j.neuropharm.2020.108242

Cited by 8 publications

(4 citation statements)

References 50 publications

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“…Consistently, this inhibition was completely rescued by cholesterol replenishment in a concentration-dependent manner. A similar behavior was observed for DH-CBD when simvastatin (a lipid lowering agent) was used in HEK 293T cells to reduce cholesterol levels . Treatment with simvastatin also decreased the DH-CBD-induced potentiation of I Gly in the spinal cord and significantly reduced DH-CBD analgesia in acute and chronic pain in mice.…”

Section: Role Of Membrane Cholesterol In the Cannabinoid Modulation O...supporting

confidence: 57%

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels

Alvarez,

Carina Alves

2024

J. Med. Chem.

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Cannabis sativa has a long history of medicinal use, dating back to ancient times. This plant produces cannabinoids, which are now known to interact with several human proteins, including Cysloop receptors for glycine (GlyR) and gamma-aminobutyric acid (GABA A R). As these channels are the primary mediators of inhibitory signals, they contribute to the diverse effects of cannabinoids on the nervous system. Evidence suggests that cannabinoid binding sites are located within the transmembrane domain, although their precise location has remained undetermined for over a decade. The process of identification of the binding site and the computational approaches employed are the main subjects of this Perspective, which includes an analysis of the most recently resolved cryo-EM structures of zebrafish GlyR bound to Δ 9 -tetrahydrocannabinol and the THC−GlyR complex obtained through molecular dynamics simulations. With this work, we aim to contribute to guiding future studies investigating the molecular basis of cannabinoid action on inhibitory channels. ■ SIGNIFICANCE• This Perspective explores the quest, begun nearly two decades ago, that led to the identification of the cannabinoid binding site in inhibitory Cys-loop channels.• The advantages and disadvantages of the methods used are critically dissected, with the goal of guiding future research on cannabinoid−channel interactions. • While progress is undeniable, numerous aspects remain shrouded, urging further exploration for a deeper understanding of how cannabinoids could produce therapeutic effects through these ion channels.

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Section: Role Of Membrane Cholesterol In the Cannabinoid Modulation O...supporting

confidence: 57%

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels

Alvarez,

Carina Alves

2024

J. Med. Chem.

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“…Considering its compensatory upregulation, GlyR could be a critical drug target for treating NP. Dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, has been widely reported to specifically enhance the function of GlyRα1 and relieve pain ( 22 , 23 , 40 , 41 ). We therefore evaluated the effects of DH-CBD on the GlyR function and the glycine neurotransmission in NP.…”

Section: Resultsmentioning

confidence: 99%

“…DH-CBD is a synthetic nonpsychoactive cannabinoid modified from tetrahydrocannabinol but does not bind to cannabinoid receptors. Thus, DH-CBD can produce significant analgesic effects without causing any psychoactive adverse effects ( 22 , 23 , 24 , 41 ). Such GlyR-hypersensitive nonpsychoactive cannabinoids may represent an efficacious clinical therapeutic strategy for treating NP.…”

Section: Discussionmentioning

confidence: 99%

The cannabinoid dehydroxylcannabidiol suppresses neuropathic pain by upregulating a spinal glycine receptor-mediated compensation mechanism

Xia

Xiao

Luo

et al. 2023

Journal of Biological Chemistry

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“…Interestingly, cholesterol seems to provide structural support to CBD binding site on the glycine receptors. Removal of membrane cholesterol by cyclodextrin ( Yao et al, 2020b ) or anti-cholesterol drug such as simvastatin ( Yao et al, 2020a ) markedly reversed THC or dehydroxyl-CBD potentiation of α1 and α3 glycine receptors by interacting with the S296 residue suggesting that cholesterol directly interact with these cannabinoids on this binding pocket. Another recent study indicates that membrane orientation of CBD and its effect on water permeability were significantly altered in the presence of cholesterol suggesting an interaction between CBD and cholesterol in lipid membranes ( Perez et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of cannabinoids on ligand-gated ion channels

2022

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Phytocannabinoids such as Δ9-tetrahydrocannabinol and cannabidiol, endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and synthetic cannabinoids such as CP47,497 and JWH-018 constitute major groups of structurally diverse cannabinoids. Along with these cannabinoids, CB1 and CB2 cannabinoid receptors and enzymes involved in synthesis and degradation of endocannabinoids comprise the major components of the cannabinoid system. Although, cannabinoid receptors are known to be involved in anti-convulsant, anti-nociceptive, anti-psychotic, anti-emetic, and anti-oxidant effects of cannabinoids, in recent years, an increasing number of studies suggest that, at pharmacologically relevant concentrations, these compounds interact with several molecular targets including G-protein coupled receptors, ion channels, and enzymes in a cannabinoid-receptor independent manner. In this report, the direct actions of endo-, phyto-, and synthetic cannabinoids on the functional properties of ligand-gated ion channels and the plausible mechanisms mediating these effects were reviewed and discussed.

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Cholesterol regulates cannabinoid analgesia through glycine receptors

Cited by 8 publications

References 50 publications

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels

The cannabinoid dehydroxylcannabidiol suppresses neuropathic pain by upregulating a spinal glycine receptor-mediated compensation mechanism

Effects of cannabinoids on ligand-gated ion channels

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