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

ABSTRACT: Recreational use of synthetic cannabinoids (SCs) is associated with desirable euphoric and relaxation effects as well as adverse effects including anxiety, agitation and psychosis. These SC-mediated actions represent a combination of potentiated cannabinoid receptor signaling and "off-target" receptor activity. The goal of this study was to compare the efficacy of various classes of SCs in stimulating CB₁ receptors and activating "off-target" transient receptor potential (TRP) channels. Cannabinoid-type 1 (CB₁) receptor activity was determined by measuring SC activation of G protein-gated inward rectifier K⁺ (GIRK) channels using a membrane potential-sensitive fluorescent dye assay. SC opening of vanilloid type-1 (TRPV1) channels was measured by recording intracellular Ca²⁺ transients. All of the SCs tested activated the GIRK channel with an efficacy of 4-fluoro MDMB-BUTINACA > 5-fluoro MDMB-PICA > MDMB-4en-PINACA ≈ WIN 55,212-2 > AB-FUBINACA > AM1220 ≈ JWH-122 N-(5-chloropentyl) > AM1248 > JWH-018 ≈ XLR-11 ≈ UR-144. The potency of the SCs at the CB₁ receptor was 5-fluoro MDMB-PICA ≈ 4-fluoro MDMB-BUTINACA > AB-FUBINACA ≈ MDMB-4en-PINACA > JWH-018 > AM1220 > XLR-11 > JWH-122 N-(5-chloropentyl) > WIN 55,212-2 ≈ UR-144 > AM1248. In contrast, when tested at a SC concentration that produced a maximal effect on the G_i/GIRK channel, only XLR-11, UR-144 and AM1220 caused a significant activation of the TRPV1 channels. The TRPV1 channel/Ca²⁺ signal measured during application of 10 μM XLR-11 was similar to the signal induced by the endocannabinoid N-arachidonoylethanolamine (AEA). Thus, while various SCs share the ability to stimulate CB₁ receptor/G_i signaling, they display limited efficacy in opening TRPV1 channels.

SUBMITTER: Andersen HK

PROVIDER: S-EPMC8374946 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Andersen Haley K HK Walsh Kenneth B KB

European journal of pharmacology 20210702

Recreational use of synthetic cannabinoids (SCs) is associated with desirable euphoric and relaxation effects as well as adverse effects including anxiety, agitation and psychosis. These SC-mediated actions represent a combination of potentiated cannabinoid receptor signaling and "off-target" receptor activity. The goal of this study was to compare the efficacy of various classes of SCs in stimulating CB<sub>1</sub> receptors and activating "off-target" transient receptor potential (TRP) channel ...[more]

PMID: 34224700

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Project description:As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy. In the closed-state simulations at 30°C, we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes flickery opening/closing. In the open-state simulations at 60°C, we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state versus the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C, we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies. Taken together, our MD simulations have offered rich structural and dynamic details beyond the static structures of TRPV1, and promising targets for future mutagenesis and functional studies of the TRPV1 channel. Proteins 2016; 84:1938-1949. © 2016 Wiley Periodicals, Inc.

Dataset Information

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

Publications

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

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