The two-pore channel TPCN2 mediates NAADP-dependent Ca(2+)-release from lysosomal stores

Pflugers Arch. 2009 Sep;458(5):891-9. doi: 10.1007/s00424-009-0690-y. Epub 2009 Jun 26.


Second messenger-induced Ca(2+)-release from intracellular stores plays a key role in a multitude of physiological processes. In addition to 1,4,5-inositol trisphosphate (IP(3)), Ca(2+), and cyclic ADP ribose (cADPR) that trigger Ca(2+)-release from the endoplasmatic reticulum (ER), nicotinic acid adenine dinucleotide phosphate (NAADP) has been identified as a cellular metabolite that mediates Ca(2+)-release from lysosomal stores. While NAADP-induced Ca(2+)-release has been found in many tissues and cell types, the molecular identity of the channel(s) conferring this release remained elusive so far. Here, we show that TPCN2, a novel member of the two-pore cation channel family, displays the basic properties of native NAADP-dependent Ca(2+)-release channels. TPCN2 transcripts are widely expressed in the body and encode a lysosomal protein forming homomers. TPCN2 mediates intracellular Ca(2+)-release after activation with low-nanomolar concentrations of NAADP while it is desensitized by micromolar concentrations of this second messenger and is insensitive to the NAADP analog nicotinamide adenine dinucleotide phosphate (NADP). Furthermore, TPCN2-mediated Ca(2+)-release is almost completely abolished when the capacity of lysosomes for storing Ca(2+) is pharmacologically blocked. By contrast, TPCN2-specific Ca(2+)-release is unaffected by emptying ER-based Ca(2+) stores. In conclusion, these findings indicate that TPCN2 is a major component of the long-sought lysosomal NAADP-dependent Ca(2+)-release channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animal Structures / metabolism
  • Animals
  • COS Cells
  • Calcium / metabolism*
  • Calcium Channels / physiology*
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cell Line
  • Chlorocebus aethiops
  • Cloning, Molecular
  • Endoplasmic Reticulum / metabolism
  • Enzyme Inhibitors / pharmacology
  • Glycosylation
  • Humans
  • Ion Channel Gating / physiology
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Lysosomes / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • NADP / analogs & derivatives*
  • NADP / metabolism
  • NADP / pharmacology
  • Sequence Homology, Amino Acid
  • Thapsigargin / pharmacology
  • Transfection
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors


  • Calcium Channels
  • Enzyme Inhibitors
  • Lysosomal-Associated Membrane Protein 1
  • TPCN1 protein, mouse
  • TPCN2 protein, mouse
  • NADP
  • Thapsigargin
  • Vacuolar Proton-Translocating ATPases
  • Calcium