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首页> 外文期刊>Biochemistry >Desensitization of the nicotinic acetylcholine receptor mainly involves a structural change in solvent-accessible regions of the polypeptide backbone.
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Desensitization of the nicotinic acetylcholine receptor mainly involves a structural change in solvent-accessible regions of the polypeptide backbone.

机译：烟碱乙酰胆碱受体的脱敏主要涉及多肽主链的溶剂可及区域的结构变化。

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摘要

The difference between infrared spectra of the nicotinic acetylcholine receptor (nAChR) recorded using the attenuated total reflectance technique in the presence and absence of carbamylcholine exhibits a complex pattern of positive and negative bands that provides a spectral map of the structural changes that occur in the nAChR upon agonist binding and subsequent desensitization. Two relatively intense bands are observed in the amide I region of the difference spectra recorded in 1H2O buffer near 1655 cm(-1) and 1620 cm(-1) that were previously interpreted in terms of either a net conversion of beta-sheet to alpha-helix or a reorientation of transmembrane alpha-helix accompanied by a change in structure of beta-sheet and/or turn [Baenziger, J. E., Miller, K. W., & Rothschild, K. J. (1993) Biochemistry 32, 5448-5454]. However, difference spectra recorded in 2H2O buffer reveal that these and other difference bands in the amide I region undergo downshifts in frequency upon peptide 1H/2H exchange that are much larger than the downshifts in frequency that are typically observed for the amide I vibrations of either alpha-helix or beta-sheet. Difference spectra recorded in 2H2O buffer within either minutes or hours of prior exposure of the nAChR to 2H2O exhibit the same amide I difference band shifts that are observed in difference spectra recorded after 3 days prior exposure of the nAChR to 2H2O. Most of the peptides that are involved in both ligand binding and the resting to desensitized conformational change and that give rise to bands in the difference spectra therefore exchange their hydrogens for deuterium on the seconds to minutes time scale. The frequencies of the difference bands, the magnitudes of the difference band shifts upon peptide 1H/2H exchange, and the rapidity of the hydrogen deuterium exchange kinetics of those structures that give rise to amide I bands in the difference spectra all suggest that the formation of a channel-inactive desensitized state results predominantly from a conformational change in solvent-accessible extramembranous regions of the polypeptide backbone as opposed to a large structural perturbation near the ion channel gate. A conformational change in the agonist binding site may be primarily responsible for channel inactivation upon desensitization.
机译：在存在和不存在氨基甲胆碱的情况下，使用衰减全反射技术记录的烟碱型乙酰胆碱受体（nAChR）的红外光谱之间的差异显示出正带和负带的复杂模式，从而提供了nAChR中发生的结构变化的光谱图在激动剂结合和随后的脱敏后。在1H2O缓冲液中记录的1655 cm（-1）和1620 cm（-1）附近的差异谱的酰胺I区域中观察到两个相对强烈的谱带，这些谱带先前是根据β-折叠净转化为α来解释的-螺旋或跨膜α-螺旋的重新定向，伴随着β-折叠和/或转向的结构变化[Baenziger，JE，Miller，KW，和Rothschild，KJ（1993）Biochemistry 32，5448-5454]。但是，记录在2H2O缓冲液中的差异光谱显示，在进行肽1H / 2H交换时，酰胺I区中的这些和其他差异带的频率下移要大得多，而对于任一信号的酰胺I振动通常观察到的频率下移要大得多。 α-螺旋或β-折叠。在将nAChR暴露于2H2O之前或之后的数分钟或数小时内，在2H2O缓冲液中记录的差异光谱显示出与在将nAChR暴露于2H2O之前3天记录的差异光谱中观察到的酰胺I差异带移相同的光谱。大部分参与配体结合和不敏感的构象变化的静止并在差异光谱中产生谱带的大多数肽因此在数秒至数分钟的时间尺度上将其氢交换为氘。差异带的频率，差异带的大小会在肽1H / 2H交换时发生位移，以及在差异谱中产生酰胺I谱带的那些结构的氢氘交换动力学的快速性都表明形成了通道失活的脱敏状态主要是由于多肽主链的溶剂可及的膜外区域的构象变化，而不是离子通道门附近的大结构扰动引起的。激动剂结合位点的构象变化可能是造成脱敏后通道失活的主要原因。

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