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Regulation of kappa opioid receptor inactivation depends on sex and cellular site of antagonist action.
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2020-11-01 , DOI: 10.1124/molpharm.120.000124
Kathryn L Reichard 1 , Keionna A Newton 1 , Zeena M G Rivera 1 , Paulo M Sotero de Menezes 1 , Selena S Schattauer 1 , Benjamin B Land 1 , Charles Chavkin 2
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The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists, norbinaltorphimine (norBNI), produces prolonged receptor inactivation by a cJun kinase mechanism. These antagonists have potential therapeutic utility in the treatment of stress disorders; however, additional preclinical characterization is necessary to understand important aspects of their action. In this study, we report that norBNI does not work as effectively in female mice as in males because of estrogen regulation of G protein receptor kinase (GRK); pretreatment of ovary-intact female mice with the selective GRK2/3 inhibitor, Compound 101, made females equally sensitive to norBNI as males. Prior observations suggested that in vivo treatment with norBNI does not produce long-lasting inhibition of KOR regulation of dopamine release in the nucleus accumbens. We assessed the persistence of norBNI receptor inactivation in subcellular compartments. Fast-scan cyclic voltammetry recordings confirmed that presynaptic inhibition of dopamine release by the KOR agonist U69,593 was not blocked by in vivo pretreatment with norBNI under conditions that prevented KOR-mediated aversion and analgesia. We employed a novel in vivo proxy sensor of KOR activation, adenovirus associated double floxed inverted–HyPerRed, and demonstrated that KOR activation stimulates cJun kinase–dependent reactive oxygen species (ROS) production in somatic regions of ventral tegmental area dopamine neurons, but did not activate ROS production in dopamine terminals. The compartment selective action helps explain how dopamine somatic, but not terminally expressed, KORs are inactivated by norBNI. These results further elucidate molecular signaling mechanisms mediating receptor-inactivating KOR antagonist action and advance medication development for this novel class of stress-resilience medications.

中文翻译:

κ阿片受体失活的调节取决于拮抗剂作用的性别和细胞位点。

受体失活 kappa 阿片受体 (KOR) 拮抗剂的原型成员,norbinaltorphimine (norBNI),通过 cJun 激酶机制产生延长的受体失活。这些拮抗剂在应激障碍的治疗中具有潜在的治疗效用;然而,需要额外的临床前表征以了解其作用的重要方面。在这项研究中,我们报告说,由于 G 蛋白受体激酶 (GRK) 的雌激素调节,norBNI 在雌性小鼠中的作用不如雄性小鼠有效;用选择性 GRK2/3 抑制剂化合物 101 预处理卵巢完整的雌性小鼠,使雌性与雄性对 norBNI 同样敏感。先前的观察表明,用norBNI 体内治疗不会对伏隔核中多巴胺释放的KOR 调节产生持久抑制。我们评估了亚细胞区室中norBNI受体失活的持续性。快速扫描循环伏安记录证实,KOR 激动剂 U69,593 对多巴胺释放的突触前抑制在阻止 KOR 介导的厌恶和镇痛的条件下用 norBNI 进行体内预处理不会被阻断。我们采用了一种新型的体内 KOR 激活代理传感器,腺病毒相关的双荧光倒置 -HyPerRed,并证明 KOR 激活刺激腹侧被盖区多巴胺神经元的体细胞区域中 cJun 激酶依赖性活性氧 (ROS) 的产生,但没有激活多巴胺末端的 ROS 产生。隔室选择性作用有助于解释多巴胺体细胞(而非终末表达)KORs 如何被norBNI 灭活。这些结果进一步阐明了介导受体失活 KOR 拮抗剂作用的分子信号传导机制,并推动了这类新型压力恢复药物的药物开发。
更新日期:2020-10-13
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