Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
JCI Insight. 2018 Jan 25;3(2). doi: 10.1172/jci.insight.97826.
We identify 2 homozygous mutations in the ε-subunit of the muscle acetylcholine receptor (AChR) in 3 patients with severe congenital myasthenia: εR218W in the pre-M1 region in 2 patients and εE184K in the β8-β9 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cys-loop receptor superfamily, while Glu184 is conserved in the α-, δ-, and ε-subunits of AChRs from all species. εR218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas εE184K reduces channel gating efficiency 11-fold but does not alter AChR cell surface expression. Determinations of the effective channel gating rate constants, combined with mutant cycle analyses, demonstrate strong energetic coupling between εR218 and εE184, and between εR218 and εE45 from the β1-β2 linker, as also observed for equivalent residues in the principal coupling pathway of the α-subunit. Thus, efficient and rapid gating of the AChR channel is achieved not only by coupling between conserved residues within the principal coupling pathway of the α-subunit, but also between corresponding residues in the ε-subunit.
我们在 3 名严重先天性肌无力患者的肌肉乙酰胆碱受体（AChR）ε 亚基中鉴定出 2 种纯合突变：2 名患者的 M1 前区 εR218W 和 1 名患者的β8-β9 接头区 εE184K。Arg218 在所有真核生物 Cys 环受体超家族成员中都保守，而 Glu184 在所有物种的 AChR 的α-、δ-和ε 亚基中都保守。εR218W 使通道门控效率降低 338 倍，细胞表面 AChR 表达降低 5 倍，而 εE184K 使通道门控效率降低 11 倍，但不改变 AChR 细胞表面表达。有效通道门控速率常数的测定，结合突变循环分析，表明 εR218 与 εE184 之间以及 εR218 与β1-β2 接头区的 εE45 之间存在强烈的能量偶联，这与α-亚基主要偶联途径中的等效残基也观察到的情况一致。因此，AChR 通道的高效和快速门控不仅通过α-亚基主要偶联途径中的保守残基之间的偶联来实现，而且还通过ε-亚基中的相应残基之间的偶联来实现。
