Cannabidiol Interactions with Voltage-Gated Sodium Channels

Sait, Lily Goodyer; Sula, Altin; Hollingworth, David; Rana, Rohini R.; Whalley, Benjamin J.; Wallace, B.A.

doi:10.1101/2020.06.15.151720

Cited by 12 publications

(25 citation statements)

References 47 publications

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“…5C. The similarities in the general effects of CBG and CBD on Nav gating and kinetics prompt us to suggest that CBG could bind at a similar location within the Nav fenestrationcentral cavity site that CBD binds (31). Additionally, the steepness of the concentration-response curves along with the physicochemical properties of CBG could also suggest a possible modulation of the membrane elasticity, which could contribute to the hyperpolarization of the inactivation curve at higher than physiologically conceivable concentrations (e.g., >15 µM), without altering voltage-dependence of activation.…”

Section: Cbg -Possible Mechanism Of Nav Inhibitionmentioning

confidence: 99%

“…It is previously shown that CBD has no molecular selectivity among the channels in the Nav superfamily (31)(32)(33). The equipotent inhibition of the Navs has been in part ascribed to the binding of CBD at the central cavity-fenestration interface within the lipid phase of the membrane.…”

Section: Cbg Is a State-dependent Inhibitor Of Sodium Currentsmentioning

confidence: 99%

“…The equipotent inhibition of the Navs has been in part ascribed to the binding of CBD at the central cavity-fenestration interface within the lipid phase of the membrane. Because this site of the Nav structure is a conserved part of the pore-domain, then interactions at this site would be structurally non-selective in nature (2,31). To determine, whether CBG shares this lack of structural selectivity, we voltage-clamped isolated rat DRG neurons (held at -100 mV and pulsed to -40 or -55 to elicit maximal current).…”

Section: Cbg Is a State-dependent Inhibitor Of Sodium Currentsmentioning

confidence: 99%

“…In this study, we sought to determine whether CBG also fits the second criteria, with respect to functionally targeting of dorsal root ganglion (DRG) excitability, at least in part, via Nav inhibition. As there are some similarities in the physicochemical properties of CBG and CBD, and because CBD has been thoroughly described with respect to Nav interactions (2,(31)(32)(33)(34), we used the prior CBD studies to guide our investigations of CBG activity in the present paper.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability

Ghovanloo

Estacion²,

Zhao³

et al. 2021

Preprint

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Cannabigerol (CBG), a non-psychotropic phytocannabinoid, is a precursor for cannabis derivatives, Δ9-tetrahydrocannabinol and cannabidiol (CBD). Like CBD, CBG has been suggested as an analgesic. A previous study reported CBG (10 µM) blocks voltage-gated sodium (Nav) currents in CNS neurons. However, the manner in which CBG inhibits Nav channels, and whether this effect contributes to CBG′s potential analgesic behavior remain unknown. Genetic and functional studies have validated Nav1.7 as an opportune target for analgesic drug development. The efforts to develop therapeutic selective Nav1.7 blockers have been unsuccessful thus far, possibly due to issues in occupancy; drugs have been administered at concentrations many folds above IC50, resulting in loss of isoform-selectivity, and increasing off-target effects. We reasoned that an alternative approach could use compounds possessing 2 important properties: ultra-hydrophobicity and functional selectivity. Hydrophobicity could enhance absorption into neuronal cells especially with local administration. Functional selectivity could reduce the likelihood of side-effects. As CBG is ultra-hydrophobic (cLogD=7.04), we sought to determine whether it also possesses functional selectivity against Nav channels that are expressed in dorsal root ganglion (DRG). We found that CBG is a ~10-fold state-dependent Nav inhibitor (KI-KR: ~2-20 µM) with an average Hill-slope of ~2. We determined that at lower concentrations, CBG predominantly blocks sodium Gmax and slows recovery from inactivation; however, as concentration is increased, CBG also hyperpolarizes Nav inactivation curves. Our modeling and multielectrode array recordings suggest that CBG attenuates DRG excitability, which is likely linked with Nav inhibition. As most Nav1.7 channels are inactivated at DRG resting membrane potential, they are more likely to be inhibited by lower CBG concentrations, suggesting functional selectivity against Nav1.7 compared to other Navs (via Gmax block).

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Section: Cbg -Possible Mechanism Of Nav Inhibitionmentioning

confidence: 99%

Section: Cbg Is a State-dependent Inhibitor Of Sodium Currentsmentioning

confidence: 99%

Section: Cbg Is a State-dependent Inhibitor Of Sodium Currentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability

Ghovanloo

Estacion²,

Zhao³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The sodium current passing through voltage-gated sodium channels (Nav) initiates action potentials in excitable cells. Nav channels are hetero-multimeric proteins composed of large ion conducting α-subunits and smaller auxiliary β-subunits (Isom et al, 1992;Catterall, 2012;Calhoun and Isom, 2014;Ghovanloo et al, 2016bGhovanloo et al, , 2018Ghovanloo and Ruben, 2020;Sait et al, 2020). The SCN5A gene encodes Nav1.5, which is the predominantly expressed Nav in the myocardium (Jiang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Biophysical Characterization of a Novel SCN5A Mutation Associated With an Atypical Phenotype of Atrial and Ventricular Arrhythmias and Sudden Death

et al. 2020

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BackgroundSudden cardiac death (SCD) is an unexpected death that occurs within an hour of the onset of symptoms. Hereditary primary electrical disorders account for up to 1/3 of all SCD cases in younger individuals and include conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are caused by mutations in the genes encoding cardiac ion channels, hence they are known as cardiac channelopathies. We identified a novel variant, T1857I, in the C-terminus of Nav1.5 (SCN5A) linked to a family with a CPVT-like phenotype characterized by atrial tachy-arrhythmias and polymorphic ventricular ectopy occurring at rest and with adrenergic stimulation, and a strong family history of SCD.ObjectiveOur goal was to functionally characterize the novel Nav1.5 variant and determine a possible link between channel gating and clinical phenotype.MethodsWe first used electrocardiogram recordings to visualize the patient cardiac electrical properties. Then, we performed voltage-clamp of transiently transfected CHO cells. Lastly, we used the ventricular/atrial models to visualize gating defects on cardiac excitability.ResultsVoltage-dependences of both activation and inactivation were right-shifted, the overlap between activation and inactivation predicted increased window currents, the recovery from fast inactivation was slowed, there was no significant difference in late currents, and there was no difference in use-dependent inactivation. The O’Hara-Rudy model suggests ventricular after depolarizations and atrial Grandi-based model suggests a slight prolongation of atrial action potential duration.ConclusionWe conclude that T1857I likely causes a net gain-of-function in Nav1.5 gating, which may in turn lead to ventricular after depolarization, predisposing carriers to tachy-arrhythmias.

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Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

et al. 2022

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Transient receptor potential vanilloid (TRPV) channels play various important roles in human physiology. As membrane proteins, these channels are modulated by their endogenous lipid environment as the recent wealth of structural studies has revealed functional and structural lipid binding sites. Additionally, it has been shown that exogenous ligands can exchange with some of these lipids to alter channel gating. Here, we used molecular dynamics simulations to examine how one member of the TRPV family, TRPV2, interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD). By computationally reconstituting TRPV2 into a typical plasma membrane environment, which includes phospholipids, cholesterol, and phosphatidylinositol (PIP) in the inner leaflet, we showed that most of the interacting surface lipids are phospholipids without strong specificity for headgroup types. Intriguingly, we observed that the C-terminal membrane proximal region of the channel binds preferentially to PIP lipids. We also modelled two structural lipids in the simulation: one in the vanilloid pocket and the other in the voltage sensor-like domain (VSLD) pocket. The simulation shows that the VSLD lipid dampens the fluctuation of the VSLD residues, while the vanilloid lipid exhibits heterogeneity both in its binding pose and in its influence on protein dynamics.Addition of CBD to our simulation system led to an open selectivity filter and a structural rearrangement that includes a clockwise rotation of the ankyrin repeat domains, TRP helix, and VSLD. Together, these results reveal the interplay between endogenous lipids and an exogenous ligand and their effect on TRPV2 stability and channel gating.

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Cannabidiol Interactions with Voltage-Gated Sodium Channels

Cited by 12 publications

References 47 publications

Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability

Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability

Biophysical Characterization of a Novel SCN5A Mutation Associated With an Atypical Phenotype of Atrial and Ventricular Arrhythmias and Sudden Death

Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

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