Edelstein S J, Schaad O, Henry E, Bertrand D, Changeux J P
Département de Biochimie, Université de Geneve, Switzerland.
Biol Cybern. 1996 Nov;75(5):361-79. doi: 10.1007/s004220050302.
Nicotinic acetylcholine receptors are transmembrane oligomeric proteins that mediate interconversions between open and closed channel states under the control of neurotransmitters. Fast in vitro chemical kinetics and in vivo electrophysiological recordings are consistent with the following multi-step scheme. Upon binding of agonists, receptor molecules in the closed but activatable resting state (the Basal state, B) undergo rapid transitions to states of higher affinities with either open channels (the Active state, A) or closed channels (the initial Inactivatable and fully Desensitized states, I and D). In order to represent the functional properties of such receptors, we have developed a kinetic model that links conformational interconversion rates to agonist binding and extends the general principles of the Monod-Wyman-Changeux model of allosteric transitions. The crucial assumption is that the linkage is controlled by the position of the interconversion transition states on a hypothetical linear reaction coordinate. Application of the model to the peripheral nicotine acetylcholine receptor (nAChR) accounts for the main properties of ligand-gating, including single-channel events, and several new relationships are predicted. Kinetic simulations reveal errors inherent in using the dose-response analysis, but justify its application under defined conditions. The model predicts that (in order to overcome the intrinsic stability of the B state and to produce the appropriate cooperativity) channel activation is driven by an A state with a Kd in the 50 nM range, hence some 140-fold stronger than the apparent affinity of the open state deduced previously. According to the model, recovery from the desensitized states may occur via rapid transit through the A state with minimal channel opening, thus without necessarily undergoing a distinct recovery pathway, as assumed in the standard 'cycle' model. Transitions to the desensitized states by low concentration 'pre-pulses' are predicted to occur without significant channel opening, but equilibrium values of IC50 can be obtained only with long pre-pulse times. Predictions are also made concerning allosteric effectors and their possible role in coincidence detection. In terms of future developments, the analysis presented here provides a physical basis for constructing more biologically realistic models of synaptic modulation that may be applied to artificial neural networks.
烟碱型乙酰胆碱受体是跨膜寡聚蛋白，在神经递质的控制下介导通道开放和关闭状态之间的相互转换。快速的体外化学动力学和体内电生理记录与以下多步骤模式一致。激动剂结合后，处于关闭但可激活的静息状态（基础状态，B）的受体分子会迅速转变为具有更高亲和力的状态，这些状态包括开放通道（活性状态，A）或关闭通道（初始失活和完全脱敏状态，I和D）。为了描述此类受体的功能特性，我们开发了一个动力学模型，该模型将构象相互转换速率与激动剂结合联系起来，并扩展了变构转换的Monod-Wyman-Changeux模型的一般原理。关键假设是这种联系由相互转换过渡态在假设的线性反应坐标上的位置控制。将该模型应用于外周尼古丁乙酰胆碱受体（nAChR）可以解释配体门控的主要特性，包括单通道事件，并且预测了一些新的关系。动力学模拟揭示了使用剂量反应分析时固有的误差，但证明了其在特定条件下的应用合理性。该模型预测（为了克服B状态的内在稳定性并产生适当的协同性）通道激活由Kd在50 nM范围内的A状态驱动，因此比先前推导的开放状态的表观亲和力强约140倍。根据该模型，从脱敏状态恢复可能通过以最小通道开放快速穿过A状态发生，因此不一定像标准“循环”模型中假设的那样经历独特的恢复途径。预测低浓度“预脉冲”向脱敏状态的转变将在没有明显通道开放的情况下发生，但只有在预脉冲时间较长时才能获得IC50的平衡值。还对变构效应剂及其在巧合检测中的可能作用进行了预测。就未来发展而言，此处提出的分析为构建更具生物学现实性的突触调制模型提供了物理基础，这些模型可应用于人工神经网络。
