NAADP-evoked Ca 2+ signals through two-pore channel-1 require arginine residues in the first S4-S5 linker

Cell Calcium. 2017 Dec;68:1-4. doi: 10.1016/j.ceca.2017.09.003. Epub 2017 Sep 29.


Two-pore channels (TPCs) are two-domain members of the voltage-gated ion channel superfamily that localize to acidic organelles. Their mechanism of activation (ligands such as NAADP/PI(3,5)P2 versus voltage) and ion selectivity (Ca2+ versus Na+) is debated. Here we report that a cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca2+ release by NAADP in intact cells. Our data affirm the role of TPCs in NAADP-mediated Ca2+ signalling and unite differing models of channel activation through identification of common domain-specific residues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Arginine / chemistry*
  • Calcium Channels / chemistry*
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects*
  • Cell Line
  • Humans
  • Mutation / genetics
  • NADP / analogs & derivatives*
  • NADP / pharmacology
  • Structure-Activity Relationship


  • Calcium Channels
  • TPCN1 protein, human
  • NADP
  • Arginine