Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Chem Biol. 2014 Jun;10(6):463-9. doi: 10.1038/nchembio.1522. Epub 2014 Apr 28.
The physiological function and molecular regulation of plasma membrane potential have been extensively studied, but how intracellular organelles sense and control membrane potential is not well understood. Using whole-organelle patch clamp recording, we show that endosomes and lysosomes are electrically excitable organelles. In a subpopulation of endolysosomes, a brief electrical stimulus elicits a prolonged membrane potential depolarization spike. The organelles have a previously uncharacterized, depolarization-activated, noninactivating Na(+) channel (lysoNaV). The channel is formed by a two-repeat six-transmembrane-spanning (2×6TM) protein, TPC1, which represents the evolutionary transition between 6TM and 4×6TM voltage-gated channels. Luminal alkalization also opens lysoNaV by markedly shifting the channel's voltage dependence of activation toward hyperpolarization. Thus, TPC1 is a member of a new family of voltage-gated Na(+) channels that senses pH changes and confers electrical excitability to organelles.
质膜电位的生理功能和分子调控已经得到了广泛的研究，但细胞内细胞器如何感知和控制膜电位还不是很清楚。我们使用全细胞器膜片钳记录技术，发现内体和溶酶体是可兴奋的细胞器。在一个内溶酶体亚群中，短暂的电刺激会引发持久的膜电位去极化尖峰。这些细胞器具有一种以前未被描述的、去极化激活的、非失活的 Na+通道（溶酶体 Na+通道，lysoNaV）。该通道由一个两重复六跨膜（2×6TM）蛋白 TPC1 形成，TPC1 代表了 6TM 和 4×6TM 电压门控通道之间的进化转变。腔内碱化也通过显著将通道的激活电压依赖性向超极化方向移动来打开 lysoNaV。因此，TPC1 是一种新的电压门控 Na+通道家族的成员，它可以感知 pH 值的变化，并赋予细胞器电兴奋性。
