Purified TPC isoforms form NAADP receptors with distinct roles for Ca(2+) signaling and endolysosomal trafficking

Curr Biol. 2010 Apr 27;20(8):703-9. doi: 10.1016/j.cub.2010.02.049. Epub 2010 Mar 25.

Abstract

Intracellular Ca(2+) signals constitute key elements in signal transduction. Of the three major Ca(2+) mobilizing messengers described, the most potent, nicotinic acid adenine dinucleotide phosphate (NAADP) is the least well understood in terms of its molecular targets [1]. Recently, we showed that heterologous expression of two-pore channel (TPC) proteins enhances NAADP-induced Ca(2+) release, whereas the NAADP response was abolished in pancreatic beta cells from Tpcn2 gene knockout mice [2]. However, whether TPCs constitute native NAADP receptors is unclear. Here we show that immunopurified endogenous TPC complexes possess the hallmark properties ascribed to NAADP receptors, including nanomolar ligand affinity [3-5]. Our study also reveals important functional differences between the three TPC isoforms. Thus, TPC1 and TPC2 both mediate NAADP-induced Ca(2+) release, but the subsequent amplification of this trigger Ca(2+) by IP(3)Rs is more tightly coupled for TPC2. In contrast, TPC3 expression suppressed NAADP-induced Ca(2+) release. Finally, increased TPC expression has dramatic and contrasting effects on endolysosomal structures and dynamics, implicating a role for NAADP in the regulation of vesicular trafficking. We propose that NAADP regulates endolysosomal Ca(2+) storage and release via TPCs and coordinates endoplasmic reticulum Ca(2+) release in a role that impacts on Ca(2+) signaling in health and disease [6].

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling / physiology*
  • Endosomes / metabolism*
  • Endosomes / ultrastructure
  • HEK293 Cells
  • Humans
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • NADP / analogs & derivatives*
  • NADP / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Strongylocentrotus purpuratus / metabolism

Substances

  • Calcium Channels
  • Protein Isoforms
  • NADP
  • NAADP
  • Calcium