Mukhtasimova Nuriya, Lee Won Yong, Wang Hai-Long, Sine Steven M
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Nature. 2009 May 21;459(7245):451-4. doi: 10.1038/nature07923. Epub 2009 Apr 1.
In the course of synaptic transmission in the brain and periphery, acetylcholine receptors (AChRs) rapidly transduce a chemical signal into an electrical impulse. The speed of transduction is facilitated by rapid ACh association and dissociation, suggesting a binding site relatively non-selective for small cations. Selective transduction has been thought to originate from the ability of ACh, over that of other organic cations, to trigger the subsequent channel-opening step. However, transitions to and from the open state were shown to be similar for agonists with widely different efficacies. By studying mutant AChRs, we show here that the ultimate closed-to-open transition is agonist-independent and preceded by two primed closed states; the first primed state elicits brief openings, whereas the second elicits long-lived openings. Long-lived openings and the associated primed state are detected in the absence and presence of an agonist, and exhibit the same kinetic signatures under both conditions. By covalently locking the agonist-binding sites in the bound conformation, we find that each site initiates a priming step. Thus, a change in binding-site conformation primes the AChR for channel opening in a process that enables selective activation by ACh while maximizing the speed and efficiency of the biological response.
在大脑和外周的突触传递过程中，乙酰胆碱受体（AChRs）迅速将化学信号转化为电冲动。ACh的快速结合和解离促进了转导速度，这表明存在一个对小阳离子相对非选择性的结合位点。选择性转导一直被认为源于ACh相较于其他有机阳离子触发后续通道开放步骤的能力。然而，对于具有广泛不同效力的激动剂，向开放状态和从开放状态转变的情况显示是相似的。通过研究突变型AChRs，我们在此表明，最终的关闭到开放转变不依赖于激动剂，且在此之前有两个预激活的关闭状态；第一个预激活状态引发短暂开放，而第二个引发长期开放。在不存在和存在激动剂的情况下都能检测到长期开放和相关的预激活状态，并且在这两种条件下都表现出相同的动力学特征。通过将激动剂结合位点共价锁定在结合构象中，我们发现每个位点都会启动一个预激活步骤。因此，结合位点构象的变化在一个过程中使AChR为通道开放做好准备，该过程能够实现ACh的选择性激活，同时最大化生物反应的速度和效率。
