PERFECTION OF A SYNAPTIC RECEPTOR - KINETICS AND ENERGETICS OF THE ACETYLCHOLINE-RECEPTOR
PERFECTION OF A SYNAPTIC RECEPTOR - KINETICS AND ENERGETICS OF THE ACETYLCHOLINE-RECEPTOR
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DOI：
10.1073/pnas.86.7.2199
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发表时间：
1989-04-01
影响因子：
11.1
通讯作者：
JACKSON, MB
中科院分区：
文献类型：
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作者：
JACKSON, MB
在优化突触传递的背景下，对乙酰胆碱受体激活的能量学和动力学进行了评估。生理需要被用作估计配基和非配基受体的闭合到开放通道平衡常数的最佳值。对乙酰胆碱与完美设计的受体结合部位的结合所产生的最大能量进行了估计。应用详细平衡原理表明，由于只有一个配体结合部位，受体将不能从乙酰胆碱结合中获得足够的能量来驱动通道构象平衡的足够大的变化。这就为第二个结合位点的存在提供了理由，而不是经常提到的协同性优势。对于两个结合位点，结合能有相当大的过剩，因此在如何利用结合能方面有相当大的灵活性。结果表明，当通道关闭时，该受体必须至少有一个与乙酰胆碱弱结合的结合部位。这对于快速终止响应是必不可少的。然而，使另一个结合部位结合得更紧密，可以增强和加速受体的激活。要同时优化反应的激活和终止，最好的解决方案是使这两个结合位点的结合亲和力不同。这定性地再现了一个实验观察结果。
The energetics and kinetics of activation of the acetylcholine receptor are evaluated in the context of optimizing rapid synaptic transmission. Physiological needs are used as the basis for estimating optimal values for the closed-to-open channel equilibrium constants of the liganded and unliganded receptor. An estimate is made of the maximum energy that can be derived from the binding of acetylcholine to a perfectly designed receptor binding site. Application of the principle of detailed balance shows that with only one ligand binding site the receptor will not be able to derive enough energy from acetylcholine binding to drive a sufficiently large change in the channel conformational equilibrium. This then provides a rationale for the existence of a second binding site, rather than the often invoked advantage of cooperativity. With two binding sites there is a considerable excess of binding energy and consequently considerable flexibility in how binding energy can be utilized. It is shown that the receptor must have at least one binding site that binds acetylcholine weakly when the channel is closed. This is essential to rapid response termination. However, making the other binding site bind more tightly can enhance and accelerate the activation of the receptor. To optimize both response activation and termination the best solution is to make the two binding sites different in their binding affinities. This qualitatively reproduces an experimental observation.