The Molecular Basis for Ca<SUP>2</SUP><SUP>+</SUP> Signalling by NAADP: Two-Pore Channels in a Complex?

Abstract

NAADP is a potent Ca2+ mobilizing messenger in a variety of cells but its molecular mechanism of action is incompletely understood. Accumulating evidence indicates that the poorly characterized two-pore channels (TPCs) in animals are NAADP sensitive Ca2+-permeable channels. TPCs localize to the endo-lysosomal system but are functionally coupled to the better characterized endoplasmic reticulum Ca2+ channels to generate physiologically relevant complex Ca2+ signals. Whether TPCs directly bind NAADP is not clear. Here we discuss the idea based on recent studies that TPCs are the pore-forming subunits of a protein complex that includes tightly associated, low molecular weight NAADP-binding proteins.

A novel Ca2+-mediated cross-talk between endoplasmic reticulum and acidic organelles: Implications for NAADP-dependent Ca2+ signalling

“…Second, the magnitude of NAADP-induced Ca 2+ currents is significantly reduced when NAADP is infused at 50-100 M, which is fully consistent with the well known desensitization of mammalian NAADP receptors in the high micromolar range [9]. Third, the Ca 2+ response to NAADP is abrogated by Ned-19, which selectively antagonizes NAADP binding to its receptor site [9,63]. Thus, NAADP triggers the activation of Ca 2+ -dependent currents in HeLa cells, thereby rendering these cells a suitable model to investigate the underlying Ca 2+ stores.…”

Two-pore channels at the intersection of endolysosomal membrane traffic

“…As such, a lower number of higher confidence candidates are identified relative to affinity purification methods and this is a key advantage. In contrast, whereas the longer list of candidates from affinity purification approaches (including TAP-tagging) must be more carefully validated to exclude false positives, casting a broader net may be critical for capturing dynamic, transient interactions that are potentially important for TPC activation [41,42,56]. Grimm et al [53] identified 26 TPC2 interactors from (HEK) human embryonic kidney cells transfected with mouse GFP–TPC2.…”

Ca2+ channels and praziquantel: A view from the free world

“…As expression of the Ca v β var subunit unusually decreased Ca v current amplitude, displacement of Ca v β var from Ca v α complexes at the cell surface would be expected to relieve this inhibition thereby increasing Ca 2+ entry into schistosomes if replicated in situ . This proposal is not in itself unreasonable: several drugs are known to target accessory subunits/modulators of ion channels (discussed in [65]), and the approach of targeting protein-protein interaction interfaces is receiving increasing attention as a therapeutic strategy. Existing examples provide precedent for targeting Ca v channels [66–68].…”