N-glycosylation of acid-sensing ion channel 1a regulates its trafficking and acidosis-induced spine remodeling.
N-glycosylation of acid-sensing ion channel 1a regulates its trafficking and acidosis-induced spine remodeling.
复制标题
DOI：
10.1523/jneurosci.5021-11.2012
复制
发表时间：
2012-03-21
期刊：
影响因子：
--
通讯作者：
Zha XM
中科院分区：
文献类型：
--
作者：
Jing L;Chu XP;Jiang YQ;Collier DM;Wang B;Jiang Q;Snyder PM;Zha XM
酸感应离子通道-1a （ASIC1a）是多种神经系统疾病的潜在治疗靶点。我们研究了ASIC1a的糖基化和转运，这两个鲜为人知的过程是决定离子通道功能结果的关键。我们发现小鼠大脑中的大多数ASIC1a完全糖基化。Tunicamycin抑制糖基化可降低ASIC1a表面运输、树突靶向和酸激活电流密度。两个糖基化位点Asn393和Asn366的n -糖基化对ASIC1a的生物发生有不同的影响。Asn393的成熟增加了ASIC1a表面和枝晶运输、pH敏感性和电流密度。相比之下，Asn366的糖基化对于ASIC1a的功能是必不可少的，并且可能是ASIC1a生物发生的限速步骤。最后，我们发现酸中毒以时间和asic1a依赖的方式降低了树突棘的密度和长度。ASIC1a N366Q显示糖基化和树突靶向性增加，增强了酸中毒引起的脊柱损失。相反，ASIC1a N393Q减少了树突靶向并显性负抑制ASIC1a电流，却产生了相反的效果。这些数据将ASIC1a的n -糖基化与其转运联系起来。更重要的是，揭示树突棘酸中毒的位点特异性作用表明，这些过程在调节突触可塑性和产生酸中毒的疾病的长期后果中发挥重要作用。
Acid-sensing ion channel-1a (ASIC1a) is a potential therapeutic target for multiple neurological diseases. We studied here ASIC1a glycosylation and trafficking, two poorly understood processes that are pivotal in determining the functional outcome of an ion channel. We found that most ASIC1a in the mouse brain was fully glycosylated. Inhibiting glycosylation with Tunicamycin reduced ASIC1a surface trafficking, dendritic targeting and acid-activated current density. N-glycosylation of the two glycosylation sites, Asn393 and Asn366, has differential effects on ASIC1a biogenesis. Maturation of Asn393 increased ASIC1a surface and dendritic trafficking, pH sensitivity and current density. In contrast, glycosylation of Asn366 was dispensable for ASIC1a function and may be a rate-limiting step in ASIC1a biogenesis. Lastly, we revealed that acidosis reduced the density and length of dendritic spines in a time- and ASIC1a-dependent manner. ASIC1a N366Q, which showed increased glycosylation and dendritic targeting, potentiated acidosis-induced spine loss. Conversely, ASIC1a N393Q, which had diminished dendritic targeting and inhibited ASIC1a current dominant-negatively, had the opposite effect. These data tie N-glycosylation of ASIC1a with its trafficking. More importantly, revealing a site-specific effect of acidosis on dendritic spines suggests an important role of these processes in regulating synaptic plasticity and long-term consequences in diseases that generate acidosis.