Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Mol Brain. 2010 Dec 21;3:39. doi: 10.1186/1756-6606-3-39.
Acid-sensing ion channel 1a (ASIC1a) is the major ASIC subunit determining acid-activated currents in brain neurons. Recent studies show that ASIC1a play critical roles in acid-induced cell toxicity. While these studies raise the importance of ASIC1a in diseases, mechanisms for ASIC1a trafficking are not well understood. Interestingly, ASIC1a interacts with PICK1 (protein interacting with C-kinase 1), an intracellular protein that regulates trafficking of several membrane proteins. However, whether PICK1 regulates ASIC1a surface expression remains unknown.
Here, we show that PICK1 overexpression increases ASIC1a surface level. A BAR domain mutant of PICK1, which impairs its lipid binding capability, blocks this increase. Lipid binding of PICK1 is also required for PICK1-induced clustering of ASIC1a. Consistent with the effect on ASIC1a surface levels, PICK1 increases ASIC1a-mediated acidotoxicity and this effect requires both the PDZ and BAR domains of PICK1.
Taken together, our results indicate that PICK1 regulates trafficking and function of ASIC1a in a lipid binding-dependent manner.
酸感应离子通道 1a（ASIC1a）是决定脑神经元中酸激活电流的主要 ASIC 亚基。最近的研究表明，ASIC1a 在酸诱导的细胞毒性中发挥着关键作用。虽然这些研究提高了 ASIC1a 在疾病中的重要性，但 ASIC1a 转运的机制还不太清楚。有趣的是，ASIC1a 与 PICK1（蛋白激酶 C 相互作用蛋白 1）相互作用，PICK1 是一种调节几种膜蛋白转运的细胞内蛋白。然而，PICK1 是否调节 ASIC1a 的表面表达仍不清楚。
在这里，我们表明 PICK1 的过表达增加了 ASIC1a 的表面水平。一种破坏其脂质结合能力的 PICK1 BAR 结构域突变体阻止了这种增加。PICK1 的脂质结合对于 PICK1 诱导的 ASIC1a 聚集也是必需的。与 ASIC1a 表面水平的影响一致，PICK1 增加了 ASIC1a 介导的酸中毒毒性，这种效应需要 PICK1 的 PDZ 和 BAR 结构域。
综上所述，我们的结果表明，PICK1 以依赖于脂质结合的方式调节 ASIC1a 的转运和功能。
