Positive modulation of a Cys-loop acetylcholine receptor by an auxiliary transmembrane subunit
Positive modulation of a Cys-loop acetylcholine receptor by an auxiliary transmembrane subunit
复制标题
DOI：
10.1038/nn.3197
复制
发表时间：
2012-10-01
影响因子：
25
通讯作者：
Bessereau, Jean-Louis
中科院分区：
文献类型：
--
作者：
Boulin, Thomas;Rapti, Georgia;Bessereau, Jean-Louis
辅助亚基通过与成孔亚基紧密特异性结合来调节电压门控和配体门控离子通道的运输、定位或门控动力学。然而，没有辅助亚基已被确定为Cys环受体超家族的成员。在这里，我们确定MOLO-1，左旋咪唑敏感的乙酰胆碱受体（L-AChRs）在秀丽隐杆线虫神经肌肉接头的正调节。MOLO-1是一种单次跨膜蛋白，含有一个单一的细胞外球状结构域-TPM结构域，存在于细菌、植物和无脊椎动物，包括非脊椎脊索动物。MOLO-1的缺失会损害运动，并使蠕虫对驱虫药左旋咪唑产生抗性。在mobo-1突变体中，L-AChR依赖的突触传递减少了一半，而突触处受体的数量和定位保持不变。在异源表达系统中，MOLO-1与L-AChR物理相互作用并直接增强通道门控而不影响单位电导。MOLO-1的鉴定扩展了Cys-环超家族中产生功能和药理学多样性的机制。
Auxiliary subunits regulate the trafficking, localization or gating kinetics of voltage- and ligand-gated ion channels by associating tightly and specifically with pore-forming subunits. However, no auxiliary subunits have been identified for members of the Cys-loop receptor superfamily. Here we identify MOLO-1, a positive regulator of levamisole-sensitive acetylcholine receptors (L-AChRs) at the Caenorhabditis elegans neuromuscular junction. MOLO-1 is a one-pass transmembrane protein that contains a single extracellular globular domain-the TPM domain, found in bacteria, plants and invertebrates, including nonvertebrate chordates. Loss of MOLO-1 impairs locomotion and renders worms resistant to the anthelmintic drug levamisole. In mobo-1 mutants, L-AChR-dependent synaptic transmission is reduced by half, while the number and localization of receptors at synapses remain unchanged. In a heterologous expression system, MOLO-1 physically interacts with L-AChRs and directly enhances channel gating without affecting unitary conductance. The identification of MOLO-1 expands the mechanisms for generating functional and pharmacological diversity in the Cys-loop superfamily.