Publications

• The voltage-gated sodium channel TPC1 confers endolysosomal excitability.

  Cang C., Bekele B., Ren D.

  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 electr ... >> More

  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. << Less

  Nat. Chem. Biol. 10:463-469(2014) [PubMed] [EuropePMC]

• TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes.

  Wang X., Zhang X., Dong X.P., Samie M., Li X., Cheng X., Goschka A., Shen D., Zhou Y., Harlow J., Zhu M.X., Clapham D.E., Ren D., Xu H.

  Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPC ... >> More

  Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPCs in endolysosomes from wild-type and TPC double-knockout mice, here we show that, in contrast to previous conclusions, TPCs are in fact sodium-selective channels activated by PI(3,5)P(2) and are not activated by NAADP. Moreover, the primary endolysosomal ion is Na(+), not K(+), as had been previously assumed. These findings suggest that the organellar membrane potential may undergo large regulatory changes and may explain the specificity of PI(3,5)P(2) in regulating the fusogenic potential of intracellular organelles. << Less

  Cell 151:372-383(2012) [PubMed] [EuropePMC]