Department of Physiology, University of California, San Francisco, San Francisco, United States.
Howard Hughes Medical Institute, San Francisco, United States.
Elife. 2019 Jul 18;8:e45187. doi: 10.7554/eLife.45187.
TMEM16F is activated by elevated intracellular Ca, and functions as a small-conductance ion channel and as a phospholipid scramblase. In contrast to its paralogs, the TMEM16A/B calcium-activated chloride channels, mouse TMEM16F has been reported as a cation-, anion-, or non-selective ion channel, without a definite conclusion. Starting with the Q559K mutant that shows no current rundown and less outward rectification in excised patch, we found that the channel shifted its ion selectivity in response to the change of intracellular Ca concentration, with an increased permeability ratio of Cl to Na (P/P) at a higher Ca level. The gradual shift of relative ion permeability did not correlate with the channel activation state. Instead, it was indicative of an alteration of electrostatic field in the permeation pathway. The dynamic change of ion selectivity suggests a charge-screening mechanism for TMEM16F ion conduction, and it provides hints to further studies of TMEM16F physiological functions.
TMEM16F 被升高的细胞内 Ca 激活，其功能作为小电导离子通道和作为一个磷脂翻转酶。与它的同源物 TMEM16A/B 钙激活氯离子通道不同，据报道，鼠 TMEM16F 是阳离子、阴离子或非选择性离子通道，没有明确的结论。从表现出无电流衰减和在膜片钳中去极化反转较少的 Q559K 突变体开始，我们发现通道响应细胞内 Ca 浓度的变化而改变其离子选择性，在更高的 Ca 水平下，Cl 对 Na 的通透性比值（P/P）增加。相对离子通透性的逐渐变化与通道激活状态无关。相反，它表明在渗透途径中静电场发生了变化。离子选择性的动态变化表明 TMEM16F 离子传导的电荷屏蔽机制，并为进一步研究 TMEM16F 的生理功能提供了线索。
