Receptor Biology Laboratory, Departments of Physiology and Biomedical Engineering and Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
J Mol Neurosci. 2010 Jan;40(1-2):70-6. doi: 10.1007/s12031-009-9260-1.
Agonist binding to Cys-loop receptors promotes a large transmembrane ion flux of several million cations or anions per second. To investigate structural bases for the dynamics (MD) simulations, X-ray crystallography, and single channel recording. MD simulations of the muscle nicotinic receptor, imbedded in a lipid bilayer with an applied transmembrane potential, reveal single cation translocation events during transient periods of channel hydration. During the simulation trajectory, cations paused for prolonged periods near several rings of anionic residues projecting from the lumen of the extracellular domain of the receptor, but subsequently the cation moved rapidly through the hydrophobic transmembrane region as the constituent alpha-helices exhibited back and forth rocking motions. Cocrystallization of acetylcholine binding protein with sulfate ions revealed coordination of five sulfates with residues from one of these charged rings; in cation-selective Cys-loop receptors this ring contains negatively charged residues, whereas in anion-selective receptors it contains positively charged residues. In the muscle nicotinic receptor, charge reversal of residues of this ring decreases unitary conductance by up to 80%. Thus in Cys-loop receptors, a series of charged rings along the ion translocation pathway concentrates hydrated ions relative to bulk solution, giving rise to charge selectivity, and then subtle motions of the hydrophobic transmembrane, coupled with transient periods of water filling, enable rapid ion flux.
激动剂与 Cys 环受体结合促进了每秒数百万个阳离子或阴离子的跨膜离子通量。为了研究动力学（MD）模拟、X 射线晶体学和单通道记录的结构基础。在跨膜电势存在的情况下，将嵌入脂质双层的肌肉烟碱受体的 MD 模拟，揭示了通道水合作用的瞬时期间的单个阳离子转运事件。在模拟轨迹中，阳离子在从受体细胞外域腔突出的几个阴离子残基环附近长时间暂停，但随后阳离子迅速穿过疏水区，因为组成的α-螺旋表现出前后摇摆运动。乙酰胆碱结合蛋白与硫酸盐的共结晶揭示了五个硫酸盐与来自这些带电环之一的残基的配位；在阳离子选择性 Cys 环受体中，该环包含带负电荷的残基，而在阴离子选择性受体中，它包含带正电荷的残基。在肌肉烟碱受体中，该环的残基的电荷反转使单位电导降低了 80%。因此，在 Cys 环受体中，离子转运途径上的一系列带电环使水合离子相对于本体溶液浓缩，从而产生电荷选择性，然后是疏水跨膜的微妙运动，加上水填充的瞬时期间，可实现快速离子通量。
