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 (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.
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Chunlei
0000000233020927
C
Cang
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Biruk
B
Bekele
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Dejian
D
Ren
D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D004558:Electric Stimulation; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010539:Permeability; D016415:Sequence Alignment; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000502:physiology*; D000097903:Two-Pore Channels
D015220:Calcium Channels; D061566:Voltage-Gated Sodium Channels; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C546784:TPCN1 protein, mouse