Key roles of hydrophobic rings of TM2 in gating of the α9α10 nicotinic cholinergic receptor
Key roles of hydrophobic rings of TM2 in gating of the α9α10 nicotinic cholinergic receptor
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DOI：
10.1038/sj.bjp.0706224
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发表时间：
2005-08-01
影响因子：
7.3
通讯作者：
Elgoyhen, AB
中科院分区：
文献类型：
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作者：
Plazas, PV;De Rosa, MJ;Elgoyhen, AB
1我们对三个疏水环进行了系统的诱变（17 '，13'和9'）在α 9 α 10烟碱胆碱能受体（nAChR）的跨膜区（TM）2内与亲水性（苏氨酸）2 α 9 α 10突变体受体的表型变化由α 9 α 10突变体受体的表达减少证明。脱敏率、ACh的EC50以及部分激动剂的功效的增加以及细胞外Ca 2+的变构调节的减少。3突变受体表现出自发开放，并且在单通道水平上，表观平均开放时间增加，而通道电导没有重大变化，因此表明通道门控增加是潜在机制。4总体而言，突变受体的表型程度在位于中心的V13 ′ T突变体的情况下更明显。5基于电鳐的电器官孔的原子模型，我们可以提出，13'和9'位侧链的相互作用是产生离子渗透的能量屏障的关键。6尽管TM2残基的作用在nAChR家族的远端α 9 α 10成员中大多是保守的，当与其他nAChR相比时，它们对通道门控的机制贡献显示出显著差异。这些差异可能起源于门控过程中的轻微差异分子内重排的不同受体，并可能导致每个nAChR与他们的生理作用。
1 We have performed a systematic mutagenesis of three hydrophobic rings (17', 13' and 9') within transmembrane region (TM) 2 of the alpha 9 alpha 10 nicotinic cholinergic receptor (nAChR) to a hydrophilic (threonine) residue and compared the properties of mutant receptors reconstituted in Xenopus laevis oocytes.2 Phenotypic changes in alpha 9 alpha 10 mutant receptors were evidenced by a decrease in the desensitization rate, an increase in both the EC50 for ACh as well as the efficacy of partial agonists and the reduction of the allosteric modulation by extracellular Ca2+.3 Mutated receptors exhibited spontaneous openings and, at the single-channel level, an increased apparent mean open time with no major changes in channel conductance, thus suggesting an increase in gating of the channel as the underlying mechanism.4 Overall, the degrees of the phenotypes of mutant receptors were more overt in the case of the centrally located V13'T mutant.5 Based on the atomic model of the pore of the electric organ of the Torpedo ray, we can propose that the interactions of side chains at positions 13' and 9' are key ones in creating an energetic barrier to ion permeation.6 In spite of the fact that the roles of the TM2 residues are mostly conserved in the distant alpha 9 alpha 10 member of the nAChR family, their mechanistic contributions to channel gating show significant differences when compared to other nAChRs. These differences might be originated from slight differential intramolecular rearrangements during gating for the different receptors and might lead each nAChR to be in tune with their physiological roles.