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

Margarida Ruas1, Katja Rietdorf, Abdelilah Arredouani

  • 1Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Current Biology : CB
|March 30, 2010
PubMed

Insights

Nicotinic acid adenine dinucleotide phosphate (NAADP) triggers calcium (Ca2+) release via two-pore channels (TPCs). This study identifies endogenous TPC complexes as NAADP receptors, revealing isoform-specific functions and roles in vesicular trafficking and Ca2+ signaling.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Physiology

Background:

  • Intracellular calcium (Ca2+) signals are crucial for cellular processes.
  • Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+ mobilizing messenger, but its molecular targets remain poorly understood.
  • Two-pore channels (TPCs) have been implicated in NAADP-induced Ca2+ release.

Purpose of the Study:

  • To investigate whether TPCs function as native NAADP receptors.
  • To characterize the functional differences between TPC isoforms in response to NAADP.
  • To explore the role of NAADP and TPCs in regulating endolysosomal structures and Ca2+ signaling.

Main Methods:

  • Immunopurification of endogenous TPC complexes.
  • Biochemical assays to determine ligand affinity.
  • Functional studies of NAADP-induced Ca2+ release in cells expressing different TPC isoforms.
  • Analysis of endolysosomal structures and dynamics.

Main Results:

  • Endogenous TPC complexes exhibit NAADP receptor properties, including nanomolar ligand affinity.
  • TPC1 and TPC2 mediate NAADP-induced Ca2+ release, with TPC2 showing tighter coupling to IP3Rs.
  • TPC3 expression suppresses NAADP-induced Ca2+ release.
  • TPC expression significantly impacts endolysosomal morphology and dynamics.

Conclusions:

  • TPCs are confirmed as endogenous NAADP receptors.
  • Distinct functional roles of TPC isoforms in Ca2+ signaling and endolysosomal regulation.
  • NAADP-mediated Ca2+ signaling via TPCs plays a significant role in vesicular trafficking and cellular homeostasis, with implications for disease.

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