Loop C and the mechanism of acetylcholine receptor-channel gating.
Loop C and the mechanism of acetylcholine receptor-channel gating.
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DOI：
10.1085/jgp.201210946
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Auerbach A
中科院分区：
文献类型：
--
作者：
Purohit P;Auerbach A
在两个神经肌肉乙酰胆碱（ACh）受体（AChR）递质结合位点的激动剂分子增加通道开放的可能性。在AChR激活的一个假设中（“引发”），每个结合位点的C环的帽化通过离散的结构途径独立地将能量转移到远端门。我们使用单通道分析，以检查实验支持这一建议，关于简短的unliganded开口，环C修饰的影响，突变的影响，无论是对或关闭的推定途径的残基，和状态模型描述电流在低[乙酰胆碱]。结果表明：（a）双配体和短暂的无配体开放是由相同的基本的全局转变产生的;（B）环C的自由基操纵并不阻止通道开放，但损害激动剂结合;（c）通路上和通路外突变都通过局部相互作用改变开放通道构象的相对稳定性而改变门控，而不是通过扰乱特定的位点-门控通讯联系;和（d）通过使用循环动力学模型，可以直接估计激动剂从低和高亲和力形式的AChR结合位点解离和结合的速率常数。我们的结论是结合位点和门之间的能量转移机制仍然是一个悬而未决的问题。
Agonist molecules at the two neuromuscular acetylcholine (ACh) receptor (AChR) transmitter-binding sites increase the probability of channel opening. In one hypothesis for AChR activation (“priming”), the capping of loop C at each binding site transfers energy independently to the distant gate over a discrete structural pathway. We used single-channel analyses to examine the experimental support for this proposal with regard to brief unliganded openings, the effects of loop-C modifications, the effects of mutations to residues either on or off the putative pathway, and state models for describing currents at low [ACh]. The results show that (a) diliganded and brief unliganded openings are generated by the same essential, global transition; (b) the radical manipulation of loop C does not prevent channel opening but impairs agonist binding; (c) both on- and off-pathway mutations alter gating by changing the relative stability of the open-channel conformation by local interactions rather than by perturbing a specific site–gate communication link; and (d) it is possible to estimate directly the rate constants for agonist dissociation from and association to both the low and high affinity forms of the AChR-binding site by using a cyclic kinetic model. We conclude that the mechanism of energy transfer between the binding sites and the gate remains an open question.
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影响因子：
3.8
作者：
Lee, Won Yong;Free, Chris R.;Sine, Steven M.
通讯作者：
Sine, Steven M.
DOI：
10.1073/pnas.251402498
发表时间：
2001-11-20
影响因子：
11.1
作者：
Grosman, C;Auerbach, A
通讯作者：
Auerbach, A
影响因子：
3.4
作者：
Cadugan, David J.;Auerbach, Anthony
通讯作者：
Auerbach, Anthony
影响因子：
11.4
作者：
Hansen, SB;Sulzenbacher, G;Bourne, Y
通讯作者：
Bourne, Y
影响因子：
5.5
作者：
AUERBACH, A
通讯作者：
AUERBACH, A