神经肌肉乙酰胆碱受体通道门控异构化的内在能量

Tapan K Nayak, Prasad G Purohit, Anthony Auerbach
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引用次数: 40

摘要

在没有激动剂的情况下,神经肌肉突触上的烟碱乙酰胆碱受体(AChR)通道很少打开,但许多不同的突变增加了无配体门控平衡常数(E0),以产生组成性活性的AChR。我们测量了两组不同突变组合的E0,并通过外推法估计了野生型achr的E0。成人型小鼠achr (-100 mV, 23°C)的估计值为7.6和7.8×10(-7)。这些值与以前使用完全不同的方法(6.5×10(-7),从单oligded门控)获得的值非常一致。E0随着去极化而降低,其程度与门控平衡常数相同,在~ 60 mV时e-fold。我们估计,在-100 mV时,无配位门控异构化的本征能为+8.4 kcal/mol (35 kJ/mol),而在没有膜电位的情况下,这种整体构象变化的本征化学能为+9.4 kcal/mol (39 kJ/mol)。胞外溶液中的Na+和K+对E0没有可测量的影响,这表明只有水占据递质结合位点时才会发生无配体门控。讨论了受体激活过程中的能量变化和离子在激动剂结合过程中的竞争性拮抗作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel.

The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel.

The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel.

The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel.

Nicotinic acetylcholine receptor (AChR) channels at neuromuscular synapses rarely open in the absence of agonists, but many different mutations increase the unliganded gating equilibrium constant (E0) to generate AChRs that are active constitutively. We measured E0 for two different sets of mutant combinations and by extrapolation estimated E0 for wild-type AChRs. The estimates were 7.6 and 7.8×10(-7) in adult-type mouse AChRs (-100 mV at 23°C). The values are in excellent agreement with one obtained previously by using a completely different method (6.5×10(-7), from monoliganded gating). E0 decreases with depolarization to the same extent as does the diliganded gating equilibrium constant, e-fold with ∼60 mV. We estimate that at -100 mV the intrinsic energy of the unliganded gating isomerization is +8.4 kcal/mol (35 kJ/mol), and that in the absence of a membrane potential, the intrinsic chemical energy of this global conformational change is +9.4 kcal/mol (39 kJ/mol). Na+ and K+ in the extracellular solution have no measureable effect on E0, which suggests that unliganded gating occurs with only water occupying the transmitter binding sites. The results are discussed with regard to the energy changes in receptor activation and the competitive antagonism of ions in agonist binding.

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