Lynx1 Shifts α4β2 Nicotinic Receptor Subunit Stoichiometry by Affecting Assembly in the Endoplasmic Reticulum
Lynx1 Shifts α4β2 Nicotinic Receptor Subunit Stoichiometry by Affecting Assembly in the Endoplasmic Reticulum
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DOI：
10.1074/jbc.m114.573667
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发表时间：
2014-11-07
影响因子：
4.8
通讯作者：
Miwa, Julie M.
中科院分区：
文献类型：
--
作者：
Nichols, Weston A.;Henderson, Brandon J.;Miwa, Julie M.
糖基磷脂酰肌醇锚定的神经毒素样受体结合蛋白，如猞猁调节剂，在拓扑学上被定位为通过结合到nAChR的细胞外部分来发挥药理学作用。一般认为，当猞猁和nAChR都在质膜上时，这些作用就会发生。在这里，我们证明了lynx1也对内质网内的α 4 β 2 nAChR产生影响。Lynx 1影响新生α 4和β 2亚基的组装，并改变到达质膜的受体群体的化学计量。此外，这些数据表明，lynx 1主要通过内质网中的这种相互作用将nAChR化学计量转变为低灵敏度（α 4）（3）（β 2）（2）五聚体，而不仅仅是通过直接调节质膜上的活性。据我们所知，这些数据代表的假设，山猫家族成员，或实际上任何糖基磷脂酰肌醇锚定蛋白，可以在细胞内发挥作用，改变组装的多亚基蛋白的第一个测试。
Glycosylphosphatidylinositol-anchored neurotoxin-like receptor binding proteins, such as lynx modulators, are topologically positioned to exert pharmacological effects by binding to the extracellular portion of nAChRs. These actions are generally thought to proceed when both lynx and the nAChRs are on the plasma membrane. Here, we demonstrate that lynx1 also exerts effects on alpha 4 beta 2 nAChRs within the endoplasmic reticulum. Lynx1 affects assembly of nascent alpha 4 and beta 2 subunits and alters the stoichiometry of the receptor population that reaches the plasma membrane. Additionally, these data suggest that lynx1 shifts nAChR stoichiometry to low sensitivity (alpha 4)(3)(beta 2)(2) pentamers primarily through this interaction in the endoplasmic reticulum, rather than solely via direct modulation of activity on the plasma membrane. To our knowledge, these data represent the first test of the hypothesis that a lynx family member, or indeed any glycosylphosphatidylinositol-anchored protein, could act within the cell to alter assembly of a multisubunit protein.