Auto-inhibition at a ligand-gated ion channel: a cross-talk between orthosteric and allosteric sites.
Auto-inhibition at a ligand-gated ion channel: a cross-talk between orthosteric and allosteric sites.
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配体门控离子通道的自抑制：正构位点和变构位点之间的串扰。
DOI：
10.1111/bph.12896
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发表时间：
2015
影响因子：
7.3
通讯作者：
Hu,Xiang-Qun
中科院分区：
文献类型：
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作者：
Hu,Xiang-Qun
背景与目的配体被认为能产生正性或负性反应，或能阻断两者。然而，发现吲哚化合物促进对5-HT 3AB受体的正面和负面作用，其显示出低水平的自发活性。本研究试图描绘这种现象背后的机制.Experimental ApproachThe自发活性V291 S 5-HT 3A受体被用来探索5-羟基吲哚（5-HoI）和5-甲氧基吲哚（5-MoI），5-HT的结构类似物，单独或与orthosteric probes.Key ResultsTwo类型的功效开关的性质，通过改变配体结构和浓度。在较低浓度下，吲哚分子5位的细微结构变化导致相反的效果。5-HoI明显引起部分变构反向激动，而5-MoI诱导变构激动。有趣的是，在更高的浓度下，这些吲哚产生了明显的自抑制作用，表现为从积极作用到消极作用的转变。5-HoI诱导从正构激动向变构反向激动转变，而5-MoI产生从变构激动向正构反向激动转变。自动抑制似乎涉及活性受体构象的正构和变构位点之间和/或非活性和活性构象之间的通讯。正构和变构反向激动和变构激动对正构拮抗的不敏感性的相加效应也被证明。Conclusions and ImplicationsTogether，结果表明吲哚结构5位的部分是5-HT 3A受体配体性质的关键决定因素，为理解配体-受体相互作用提供了新的见解。
Background and PurposeA ligand is believed to produce either positive or negative responses, or to block both of them. However, an indole compound was found to promote both positive and negative effects at the 5‐HT3AB receptor, which displays a low level of spontaneous activity. The present study attempted to delineate the mechanisms underlying this phenomenon.Experimental ApproachThe spontaneously active V291S 5‐HT3A receptor was used to explore the properties of 5‐hydroxyindole (5‐HoI) and 5‐methoxyindole (5‐MoI), structural analogues of 5‐HT, either alone or in combination with orthosteric probes.Key ResultsTwo types of efficacy switching were initiated by altering ligand structure and concentration. At lower concentrations, a subtle structural change at position 5 of the indole molecule resulted in opposite effects. 5‐HoI apparently elicited partial allosteric inverse agonism, whereas 5‐MoI induced allosteric agonism. Interestingly, at a higher concentration, these indoles produced distinct auto‐inhibition, manifested as a switch from positive to negative effects. 5‐HoI induced a transition from orthosteric agonism to allosteric inverse agonism, whereas 5‐MoI produced a shift from allosteric agonism to orthosteric inverse agonism. The auto‐inhibition appears to involve communication between orthosteric and allosteric sites of the active receptor conformation and/or between inactive and active conformations. An additive effect of orthosteric and allosteric inverse agonism and insensitivity of allosteric agonism to orthosteric antagonism were also demonstrated.Conclusions and ImplicationsTogether, the results suggest that the moiety at position 5 of the indole structure is a critical determinant of a ligand's properties at the 5‐HT3A receptor, providing new insights into understanding ligand–receptor interactions.