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The voltage-gated sodium channel TPC1 confers endolysosomal excitability

Abstract

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.

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Figure 1: A new organellar voltage-gated Na+ channel.
Figure 2: TPC1, but not TPC2, forms a lysoNaV-like voltage-gated channel.
Figure 3: Both lysoNaV and TPC1 are pH sensitive.
Figure 4: TPC1 is Na+ selective.
Figure 5: Charged residues in the S4 domains contribute to the voltage-sensitivity of TPC1.
Figure 6: TPC1 confers endolysosomal excitability.

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Acknowledgements

We thank members of the Ren lab for discussion and support and D. Clapham for suggestions. This work was funded, in part, by the American Heart Association, the US National Institutes of Health (grants 2R01NS055293 and 5R01NS074257 to D.R.) and the University of Pennsylvania Research Foundation.

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C.C. developed the hypothesis that TPC1 is a depolarization-activated Na+ channel and contributed all of the patch-clamp recording data, and C.C. and D.R. designed the experiments. D.R. supervised the research, B.B. and D.R. developed the cDNA constructs and the mouse model, and C.C. and D.R. wrote the manuscript.

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Correspondence to Chunlei Cang or Dejian Ren.

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The authors declare no competing financial interests.

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Cang, C., Bekele, B. & Ren, D. The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nat Chem Biol 10, 463–469 (2014). https://doi.org/10.1038/nchembio.1522

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