Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor
Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor
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DOI：
10.1073/pnas.1415013111
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发表时间：
2014-12-23
影响因子：
11.1
通讯作者：
Traynor, John R.
中科院分区：
文献类型：
--
作者：
Livingston, Kathryn E.;Traynor, John R.
阿片受体（mu-opioid receptor, MOPr）是所有临床使用的阿片类药物的作用部位，其正变构调节是治疗疼痛的一种潜在方法。我们最近报道了一类G蛋白偶联受体（GPCR） MOPr （mu- pam）的阳性变构调节剂。本研究旨在通过比较阿片配体结构调节的程度来研究变构的机制。为了做到这一点，我们研究了mu-PAM， BMS-986122与化学上不同范围的MOPr正构配体的相互作用。总的来说，对于完全激动剂，BMS-986122增强了结合亲和力和激活G蛋白的效力，但最大作用没有改变。相比之下，包括吗啡在内的低效激动剂对结合亲和力的改变不敏感，刺激G蛋白的效力几乎没有变化。相反，最大G蛋白刺激增加。拮抗剂对BMS-986122的调节作用无反应。钠是一种已知的内源性MOPr变构调节剂，可以改变正构激动剂的亲和力和效力。正构配体对BMS-986122的敏感性与其对NaCl的敏感性密切相关。此外，BMS-986122降低了NaCl以变抗方式调节激动剂结合的能力。总体而言，BMS-986122表现出明显的探针依赖性，这是基于正构配体的有效性，可以用Monod-Wyman-Changeux变构双态模型来解释。此外，Na+离子结合位点的破坏可能是a类gpcr变构调节的共同机制。
Positive allosteric modulation of the mu-opioid receptor (MOPr), the site of action of all clinically used opioids, represents a potential approach for the management of pain. We recently reported on positive allosteric modulators of MOPr (mu-PAMs), a class A G protein coupled receptor (GPCR). This study was designed to examine the mechanism of allostery by comparing the degree to which opioid ligand structure governs modulation. To do this we examined the interaction of the mu-PAM, BMS-986122, with a chemically diverse range of MOPr orthosteric ligands. Generally, for full agonists BMS-986122 enhanced the binding affinity and potency to activate G protein with no alteration in the maximal effect. In contrast, lower efficacy agonists including morphine were insensitive to alterations in binding affinity and showed little to no change in potency to stimulate G protein. Instead, there was an increase in maximal G protein stimulation. Antagonists were unresponsive to the modulatory effects of BMS-986122. Sodium is a known endogenous allosteric modulator of MOPr and alters orthosteric agonist affinity and efficacy. The sensitivity of an orthosteric ligand to BMS-986122 was strongly correlated with its sensitivity to NaCl. In addition, BMS-986122 decreased the ability of NaCl to modulate agonist binding in an allosteric fashion. Overall, BMS-986122 displayed marked probe dependence that was based upon the efficacy of the orthosteric ligand and can be explained using the Monod-Wyman-Changeux two-state model of allostery. Furthermore, disruption of the Na+ ion binding site may represent a common mechanism for allosteric modulation of class A GPCRs.