Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling |
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| Authors: | Eugen Brailoiu Dev Churamani Xinjiang Cai Michael G. Schrlau G. Cristina Brailoiu Xin Gao Robert Hooper Michael J. Boulware Nae J. Dun Jonathan S. Marchant Sandip Patel |
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| Affiliation: | 1.Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140;2.Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK;3.Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710;4.Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA 19104;5.Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455 |
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| Abstract: | Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP. |
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