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Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking
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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Cell Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861162/ https://www.ncbi.nlm.nih.gov/pubmed/20346675 http://dx.doi.org/10.1016/j.cub.2010.02.049 |
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author | Ruas, Margarida Rietdorf, Katja Arredouani, Abdelilah Davis, Lianne C. Lloyd-Evans, Emyr Koegel, Heidi Funnell, Timothy M. Morgan, Anthony J. Ward, John A. Watanabe, Keiko Cheng, Xiaotong Churchill, Grant C. Zhu, Michael X. Platt, Frances M. Wessel, Gary M. Parrington, John Galione, Antony |
author_facet | Ruas, Margarida Rietdorf, Katja Arredouani, Abdelilah Davis, Lianne C. Lloyd-Evans, Emyr Koegel, Heidi Funnell, Timothy M. Morgan, Anthony J. Ward, John A. Watanabe, Keiko Cheng, Xiaotong Churchill, Grant C. Zhu, Michael X. Platt, Frances M. Wessel, Gary M. Parrington, John Galione, Antony |
author_sort | Ruas, Margarida |
collection | PubMed |
description | 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]. |
format | Text |
id | pubmed-2861162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28611622010-05-06 Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking Ruas, Margarida Rietdorf, Katja Arredouani, Abdelilah Davis, Lianne C. Lloyd-Evans, Emyr Koegel, Heidi Funnell, Timothy M. Morgan, Anthony J. Ward, John A. Watanabe, Keiko Cheng, Xiaotong Churchill, Grant C. Zhu, Michael X. Platt, Frances M. Wessel, Gary M. Parrington, John Galione, Antony Curr Biol Report 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]. Cell Press 2010-04-27 /pmc/articles/PMC2861162/ /pubmed/20346675 http://dx.doi.org/10.1016/j.cub.2010.02.049 Text en © 2010 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license |
spellingShingle | Report Ruas, Margarida Rietdorf, Katja Arredouani, Abdelilah Davis, Lianne C. Lloyd-Evans, Emyr Koegel, Heidi Funnell, Timothy M. Morgan, Anthony J. Ward, John A. Watanabe, Keiko Cheng, Xiaotong Churchill, Grant C. Zhu, Michael X. Platt, Frances M. Wessel, Gary M. Parrington, John Galione, Antony Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking |
title | Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking |
title_full | Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking |
title_fullStr | Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking |
title_full_unstemmed | Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking |
title_short | Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca(2+) Signaling and Endolysosomal Trafficking |
title_sort | purified tpc isoforms form naadp receptors with distinct roles for ca(2+) signaling and endolysosomal trafficking |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861162/ https://www.ncbi.nlm.nih.gov/pubmed/20346675 http://dx.doi.org/10.1016/j.cub.2010.02.049 |
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