First and second transmembrane segments of α3, α4, β2, and β4 nicotinic acetylcholine receptor subunits influence the efficacy and potency of nicotine
First and second transmembrane segments of α3, α4, β2, and β4 nicotinic acetylcholine receptor subunits influence the efficacy and potency of nicotine
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DOI：
10.1124/mol.61.6.1416
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发表时间：
2002-06
影响因子：
3.6
通讯作者：
Ray Rush;A. Kuryatov;M. Nelson;J. Lindstrom
中科院分区：
文献类型：
--
作者：
Ray Rush;A. Kuryatov;M. Nelson;J. Lindstrom
通过α3/α4亚基嵌合体的研究，人烟碱乙酰胆碱受体（nAChR）的前三个跨膜区段（M1-M3）涉及确定尼古丁的功效（[Kuryatov et al.，2000 a][1]）。尼古丁对α4β2 nAChR完全有效，对α3β2 nAChR部分有效。现在，我们在α4和α3亚基之间分别交换了226（M1）、258（M2）和262（M2）位的三个氨基酸。此外，在224（M1）、226（M1）和254（M2）位（使用α亚基编号）的β2和β4亚基中进行了类似的交换。这些突变的nAChRs在非洲爪蟾卵母细胞中的表达表明，突变的M1氨基酸是重要的影响乙酰胆碱和尼古丁的效力。假设这些M1氨基酸影响nAChR的静息和活化状态之间的稳定性。M2氨基酸改变了尼古丁的功效，通常不会改变其效力。当位于α亚基M2区258位的残基为缬氨酸（与α3亚基相同）时，产生的nAChR对尼古丁表现出部分功效，且具有电压依赖性。因此，我们认为这些M2氨基酸有助于在α3β2 nAChR通道中形成尼古丁结合位点，从而导致低亲和力通道阻滞，导致尼古丁对该nAChR的疗效较低。[1]：#ref-18
The first three transmembrane segments (M1–M3) of human nicotinic acetylcholine receptors (nAChRs) have been implicated in determining the efficacy of nicotine by studies of α3/α4 subunit chimeras ([Kuryatov et al., 2000a][1]). Nicotine has full efficacy on the α4β2 nAChR and partial efficacy on the α3β2 nAChR. Now, we have exchanged individually three amino acids between the α4 and the α3 subunits at positions 226(M1), 258(M2), and 262(M2). Also, similar exchanges were made in the β2 and β4 subunits at positions 224(M1), 226(M1), and 254(M2) (using α subunit numbering). Expression of these mutated nAChRs in Xenopus laevis oocytes showed that the mutated M1 amino acids were important in influencing the potency of ACh and nicotine. It is hypothesized that these M1 amino acids affect the stability between the resting and activated states of the nAChR. M2 amino acids altered the efficacy of nicotine, usually without altering its potency. When the residue located at position 258 in the M2 region of the α subunit was valine (as in the α3 subunit), the resulting nAChR exhibited partial efficacy for nicotine that was voltage-dependent. Therefore, we believe that these M2 amino acids contribute to the formation of a binding site for nicotine in the α3β2 nAChR channel, which results in a low-affinity channel block, causing the lower efficacy of nicotine on this nAChR. [1]: #ref-18