The voltage-gated sodium channel TPC1 confers endolysosomal excitability

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Channels / genetics
  • Calcium Channels / physiology*
  • Electric Stimulation
  • Endosomes / metabolism*
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Intracellular Membranes / metabolism
  • Ion Channel Gating / physiology*
  • Lysosomes / metabolism*
  • Macrophages, Peritoneal / metabolism
  • Membrane Potentials / physiology
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Permeability
  • Sequence Alignment
  • Voltage-Gated Sodium Channels / genetics
  • Voltage-Gated Sodium Channels / physiology*


  • Calcium Channels
  • TPCN1 protein, human
  • TPCN1 protein, mouse
  • Voltage-Gated Sodium Channels