Lape Remigijus, Colquhoun David, Sivilotti Lucia G
Department of Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK.
Nature. 2008 Aug 7;454(7205):722-7. doi: 10.1038/nature07139. Epub 2008 Jul 16.
Partial agonists are ligands that bind to receptors but produce only a small maximum response even at concentrations where all receptors are occupied. In the case of ligand-activated ion channels, it has been supposed since 1957 that partial agonists evoke a small response because they are inefficient at eliciting the change of conformation between shut and open states of the channel. We have investigated partial agonists for two members of the nicotinic superfamily-the muscle nicotinic acetylcholine receptor and the glycine receptor-and find that the open-shut reaction is similar for both full and partial agonists, but the response to partial agonists is limited by an earlier conformation change ('flipping') that takes place while the channel is still shut. This has implications for the interpretation of structural studies, and in the future, for the design of partial agonists for therapeutic use.
部分激动剂是一类与受体结合的配体，即使在所有受体都被占据的浓度下，也只能产生很小的最大反应。对于配体激活的离子通道，自1957年以来人们就认为，部分激动剂引发的反应较小是因为它们在引发通道关闭和开放状态之间的构象变化方面效率低下。我们研究了烟碱超家族的两个成员——肌肉型烟碱乙酰胆碱受体和甘氨酸受体——的部分激动剂，发现完全激动剂和部分激动剂的开闭反应相似，但对部分激动剂的反应受到通道仍处于关闭状态时发生的早期构象变化（“翻转”）的限制。这对结构研究的解释有影响，并且在未来对治疗用部分激动剂的设计也有影响。
