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NAADP mobilizes calcium from acidic organelles through two-pore channels

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      Abstract

      Ca2+ mobilization from intracellular stores represents an important cell signaling process 1 which is regulated, in mammalian cells, by inositol 1,4,5-trisphosphate (InsP3), cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP3 and cADPR release Ca2+ from sarco / endoplasmic reticulum (S/ER) stores through activation of InsP3 and ryanodine receptors (InsP3Rs and RyRs). By contrast, the nature of the intracellular stores targeted by NAADP and molecular identity of the NAADP receptors remain controversial 1,2, although evidence indicates that NAADP mobilizes Ca2+ from lysosome-related acidic compartments 3,4. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with TPC1 and TPC3 being expressed on endosomal and TPC2 on lysosomal membranes. Membranes enriched with TPC2 exhibit high affinity NAADP binding and TPC2 underpins NAADP-induced Ca2+ release from lysosome-related stores that is subsequently amplified by Ca2+-induced Ca2+ release via InsP3Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but only attenuated by depleting ER Ca2+ stores or blocking InsP3Rs. Thus, TPCs form NAADP receptors that release Ca2+ from acidic organelles, which can trigger additional Ca2+ signals via S/ER. TPCs therefore provide new insights into the regulation and organization of Ca2+ signals in animal cells and will advance our understanding of the physiological role of NAADP.

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      Calcium signalling: dynamics, homeostasis and remodelling.

      Ca2+ is a highly versatile intracellular signal that operates over a wide temporal range to regulate many different cellular processes. An extensive Ca2+-signalling toolkit is used to assemble signalling systems with very different spatial and temporal dynamics. Rapid highly localized Ca2+ spikes regulate fast responses, whereas slower responses are controlled by repetitive global Ca2+ transients or intracellular Ca2+ waves. Ca2+ has a direct role in controlling the expression patterns of its signalling systems that are constantly being remodelled in both health and disease.
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        BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.

        The BayGenomics gene-trap resource (http://baygenomics.ucsf.edu) provides researchers with access to thousands of mouse embryonic stem (ES) cell lines harboring characterized insertional mutations in both known and novel genes. Each cell line contains an insertional mutation in a specific gene. The identity of the gene that has been interrupted can be determined from a DNA sequence tag. Approximately 75% of our cell lines contain insertional mutations in known mouse genes or genes that share strong sequence similarities with genes that have been identified in other organisms. These cell lines readily transmit the mutation to the germline of mice and many mutant lines of mice have already been generated from this resource. BayGenomics provides facile access to our entire database, including sequence tags for each mutant ES cell line, through the World Wide Web. Investigators can browse our resource, search for specific entries, download any portion of our database and BLAST sequences of interest against our entire set of cell line sequence tags. They can then obtain the mutant ES cell line for the purpose of generating knockout mice.
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          NAADP mobilizes Ca(2+) from reserve granules, lysosome-related organelles, in sea urchin eggs.

          Nicotinic acid adenine dinucleotide phosphate (NAADP) mobilizes Ca(2+) in many cells and species. Unlike other Ca(2+)-mobilizing messengers, NAADP mobilizes Ca(2+) from an unknown store that is not the endoplasmic reticulum, the store traditionally associated with messenger-mediated Ca(2+) signaling. Here, we demonstrate the presence of a Ca(2+) store in sea urchin eggs mobilized by NAADP that is dependent on a proton gradient maintained by an ATP-dependent vacuolar-type proton pump. Moreover, we provide pharmacological and biochemical evidence that this Ca(2+) store is the reserve granule, the functional equivalent of a lysosome in the sea urchin egg. These findings represent an unsuspected mechanism for messenger-mediated Ca(2+) release from lysosome-related organelles.
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            Author and article information

            Affiliations
            [1]Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland UK
            [2]Department of Pharmacology, University of Oxford, Oxford, UK
            [3]Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA
            [4]College of Life Sciences, Peking University, Beijing, China
            [5]Department of Neuroscience and Center for Molecular Neurobiology, The Ohio State University, Columbus, OH, USA
            [6]MRC Harwell, Oxfordshire, UK
            Author notes
            [*]

            Address correspondence to: Dr. Michael X. Zhu, Center for Molecular Neurobiology, The Ohio State University, 168 Rightmire Hall, 1060 Carmack Road, Columbus, OH 43210, USA. Tel: (614)292-8173, Fax: (614)292-5379, email: zhu.55@123456osu.edu

            [¶]

            Equal contributing authors

            Journal
            0410462
            6011
            Nature
            Nature
            0028-0836
            1476-4687
            6 April 2009
            22 April 2009
            28 May 2009
            28 November 2009
            : 459
            : 7246
            : 596-600
            2761823
            19387438
            10.1038/nature08030
            nihpa107904
            Funding
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: R21 NS056942-01 ||NS
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: R01 NS042183-04 ||NS
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: R01 DK081654-01A1 ||DK
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: P30 NS045758-059003 ||NS
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: P30 NS045758-05 ||NS
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