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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G_i Complex Structures.

ABSTRACT: Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G_i, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

SUBMITTER: Hua T

PROVIDER: S-EPMC7898353 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G<sub>i</sub> Complex Structures.

Hua Tian T Li Xiaoting X Wu Lijie L Iliopoulos-Tsoutsouvas Christos C Wang Yuxia Y Wu Meng M Shen Ling L Brust Christina A CA Nikas Spyros P SP Song Feng F Song Xiyong X Yuan Shuguang S Sun Qianqian Q Wu Yiran Y Jiang Shan S Grim Travis W TW Benchama Othman O Stahl Edward L EL Zvonok Nikolai N Zhao Suwen S Bohn Laura M LM Makriyannis Alexandros A Liu Zhi-Jie ZJ

Cell 20200130 4

Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the ...[more]

PMID: 32004463

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Project description:Introduction: Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore, an urgent need to identify safe and effective therapeutics that can attenuate fentanyl-induced respiratory depression. Identification of effective alternate analgesic strategies that lessen the respiratory depression associated with narcotics would also help improve current strategies for pain management. Our laboratory recently reported that the G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppressed chemotherapy-induced neuropathic nociception and attenuated both morphine tolerance and physical dependence in paclitaxel-treated mice. However, the impact of LY2828360 on other undesirable side effects of opioids, such as opioid-induced respiratory depression, remains unknown. Materials and Methods: We used whole-body plethysmography to assess the impact of the CB2 cannabinoid agonist LY2828360 on fentanyl-induced respiratory depression using wild-type (WT) and CB2 knockout (CB2KO) mice. Results: Fentanyl reduced minute ventilation and respiratory frequency without altering tidal volume in both WT and CB2KO mice. In WT mice, the high dose of fentanyl (0.2 mg/kg intraperitoneal [i.p.]) produced a greater suppression of respiratory parameters compared with the low dose of fentanyl (0.1 mg/kg i.p.). Coadministration of a behaviorally active dose of LY2828360 (3 mg/kg i.p.) with fentanyl (0.2 mg/kg i.p.) attenuated fentanyl-induced respiratory depression in WT mice. Notably, LY2828360 (3 mg/kg i.p.) did not attenuate fentanyl-induced respiratory depression in CB2KO mice, consistent with mediation by CB2 receptors. Moreover, LY2828360 (3 mg/kg i.p.) alone lacked intrinsic effects on respiratory parameters in either WT or CB2KO mice. Conclusion: The combination of a CB2 agonist with fentanyl may represent a safer adjunctive therapeutic strategy compared with a narcotic analgesic alone by attenuating the development of opioid-induced respiratory depression. Moreover, the CB2 agonist, administered alone, did not alter respiration. Our findings suggest that the CB2 cannabinoid agonist LY2828360 may provide CB2-mediated protection against fentanyl-induced respiratory depression, a detrimental and unwanted side effect of opioid use and abuse.

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G_i Complex Structures.

Publications

Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G<sub>i</sub> Complex Structures.

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.

Publications

Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G<sub>i</sub> Complex Structures.

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OmicsDI is part of the ELIXIR infrastructure

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G_i Complex Structures.