The voltage-gated sodium channel TPC1 confers endolysosomal excitability

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 (lysoNa(v)). The channel is formed by a two-repeat six-transmembrane-spanning (2x6TM) protein, TPC1, which represents the evolutionary transition between 6TM and 4x6TM 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 Isle channels that senses pH changes and confers electrical excitability to organelles.