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Echinobase
ECB-ART-41570
Curr Biol 2010 Apr 27;208:703-9. doi: 10.1016/j.cub.2010.02.049.
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Purified TPC isoforms form NAADP receptors with distinct roles for Ca(2+) signaling and endolysosomal trafficking.

Ruas M , Rietdorf K , Arredouani A , Davis LC , Lloyd-Evans E , Koegel H , Funnell TM , Morgan AJ , Ward JA , Watanabe K , Cheng X , Churchill GC , Zhu MX , Platt FM , Wessel GM , Parrington J , Galione A .


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].

PubMed ID: 20346675
PMC ID: PMC2861162
Article link: Curr Biol
Grant support: [+]

Genes referenced: LOC115917870 LOC115919910 LOC115925116 LOC574780 LOC576539 LOC594566 tpc2 tpcn1 tpcn3
Antibodies: tpc2 Ab1 tpcn1 Ab1 tpcn3 Ab1


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References [+] :
Aarhus, Activation and inactivation of Ca2+ release by NAADP+. 1996, Pubmed, Echinobase