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Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors.

ABSTRACT: Design of cannabinergic subtype selective ligands is challenging because of high sequence and structural similarities of cannabinoid receptors (CB₁ and CB₂). We hypothesize that the subtype selectivity of designed selective ligands can be explained by the ligand binding to the conformationally distinct states between cannabinoid receptors. Analysis of ~ 700 μs of unbiased simulations using Markov state models and VAMPnets identifies the similarities and distinctions between the activation mechanism of both receptors. Structural and dynamic comparisons of metastable intermediate states allow us to observe the distinction in the binding pocket volume change during CB₁ and CB₂ activation. Docking analysis reveals that only a few of the intermediate metastable states of CB₁ show high affinity towards CB₂ selective agonists. In contrast, all the CB₂ metastable states show a similar affinity for these agonists. These results mechanistically explain the subtype selectivity of these agonists by deciphering the activation mechanism of cannabinoid receptors.

SUBMITTER: Dutta S

PROVIDER: S-EPMC10163236 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors.

Dutta Soumajit S Shukla Diwakar D

Communications biology 20230505 1

Design of cannabinergic subtype selective ligands is challenging because of high sequence and structural similarities of cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>). We hypothesize that the subtype selectivity of designed selective ligands can be explained by the ligand binding to the conformationally distinct states between cannabinoid receptors. Analysis of ~ 700 μs of unbiased simulations using Markov state models and VAMPnets identifies the similarities and distinctions between ...[more]

PMID: 37147497

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Project description:Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren's syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

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Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors.

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Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors.

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