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Derepression may masquerade as activation in ligand-gated ion channels
Nature Communications ( IF 14.7 ) Pub Date : 2023-04-05 , DOI: 10.1038/s41467-023-36770-z
Christian J G Tessier 1 , Johnathon R Emlaw 1 , Raymond M Sturgeon 1 , Corrie J B daCosta 1
Affiliation  

Agonists are ligands that bind to receptors and activate them. In the case of ligand-gated ion channels, such as the muscle-type nicotinic acetylcholine receptor, mechanisms of agonist activation have been studied for decades. Taking advantage of a reconstructed ancestral muscle-type β-subunit that forms spontaneously activating homopentamers, here we show that incorporation of human muscle-type α-subunits appears to repress spontaneous activity, and furthermore that the presence of agonist relieves this apparent α-subunit-dependent repression. Our results demonstrate that rather than provoking channel activation/opening, agonists may instead ‘inhibit the inhibition’ of intrinsic spontaneous activity. Thus, agonist activation may be the apparent manifestation of agonist-induced derepression. These results provide insight into intermediate states that precede channel opening and have implications for the interpretation of agonism in ligand-gated ion channels.



中文翻译:

去阻遏可能伪装成配体门控离子通道的激活

激动剂是与受体结合并激活它们的配体。在配体门控离子通道的情况下,例如肌肉型烟碱乙酰胆碱受体,激动剂激活机制已经研究了几十年。利用形成自发激活同型五聚体的重建祖先肌肉型 β-亚基,在这里我们表明人类肌肉型 α-亚基的掺入似乎抑制自发活动,而且激动剂的存在减轻了这种明显的 α-亚基- 依赖性镇压。我们的结果表明,激动剂可能不会引发通道激活/开放,而是“抑制”内在自发活动。因此,激动剂激活可能是激动剂诱导的去抑制的明显表现。

更新日期:2023-04-06
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