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      NAADP and the two-pore channel protein 1 participate in the acrosome reaction in mammalian spermatozoa

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          Abstract

          A TPCN1 gene–deficient mouse strain is used to show that two convergent working NAADP-dependent pathways with nonoverlapping activation and self-inactivation profiles for distinct NAADP concentrations drive acrosomal exocytosis, by which TPC1 is central for the pathway activated by low-micromolar NAADP concentrations.

          Abstract

          The functional relationship between the formation of hundreds of fusion pores during the acrosome reaction in spermatozoa and the mobilization of calcium from the acrosome has been determined only partially. Hence, the second messenger NAADP, promoting efflux of calcium from lysosome-like compartments and one of its potential molecular targets, the two-pore channel 1 (TPC1), were analyzed for its involvement in triggering the acrosome reaction using a TPCN1 gene–deficient mouse strain. The present study documents that TPC1 and NAADP-binding sites showed a colocalization at the acrosomal region and that treatment of spermatozoa with NAADP resulted in a loss of the acrosomal vesicle that showed typical properties described for TPCs: Registered responses were not detectable for its chemical analogue NADP and were blocked by the NAADP antagonist trans-Ned-19. In addition, two narrow bell-shaped dose-response curves were identified with maxima in either the nanomolar or low micromolar NAADP concentration range, where TPC1 was found to be responsible for activating the low affinity pathway. Our finding that two convergent NAADP-dependent pathways are operative in driving acrosomal exocytosis supports the concept that both NAADP-gated cascades match local NAADP concentrations with the efflux of acrosomal calcium, thereby ensuring complete fusion of the large acrosomal vesicle.

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          Caveolin, a protein component of caveolae membrane coats.

          K. Rothberg, J Heuser, W C Donzell … (1992)
          Caveolae have been implicated in the transcytosis of macromolecules across endothelial cells and in the receptor-mediated uptake of 5-methyltetrahydrofolate. Structural studies indicate that caveolae are decorated on their cytoplasmic surface by a unique array of filaments or strands that form striated coatings. To understand how these nonclathrin-coated pits function, we performed structural analysis of the striated coat and searched for the molecular component(s) of the coat material. The coat cannot be removed by washing with high salt; however, exposure of membranes to cholesterol-binding drugs caused invaginated caveolae to flatten and the striated coat to disassemble. Antibodies directed against a 22 kd substrate for v-src tyrosine kinase in virus-transformed chick embryo fibroblasts decorated the filaments, suggesting that this molecule is a component of the coat. We have named the molecule caveolin. Caveolae represent a third type of coated membrane specialization that is involved in molecular transport.
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            NAADP mobilizes calcium from acidic organelles through two-pore channels

            Peter J. Calcraft, Abdelilah Arredouani, Margarida Ruas … (2009)
            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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              TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes.

              Xiang Q Wang, Xiaoli Zhang, Xian-Ping Dong … (2012)
              Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPCs in endolysosomes from wild-type and TPC double-knockout mice, here we show that, in contrast to previous conclusions, TPCs are in fact sodium-selective channels activated by PI(3,5)P(2) and are not activated by NAADP. Moreover, the primary endolysosomal ion is Na(+), not K(+), as had been previously assumed. These findings suggest that the organellar membrane potential may undergo large regulatory changes and may explain the specificity of PI(3,5)P(2) in regulating the fusogenic potential of intracellular organelles. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Julie Brill: Role: Monitoring Editor
                Journal
                Journal ID (nlm-ta): Mol Biol Cell
                Journal ID (iso-abbrev): Mol. Biol. Cell
                Journal ID (hwp): molbiolcell
                Journal ID (pmc): mbc
                Journal ID (publisher-id): Mol. Bio. Cell
                Title: Molecular Biology of the Cell
                Publisher: The American Society for Cell Biology
                ISSN (Print): 1059-1524
                ISSN (Electronic): 1939-4586
                Publication date (Print): 15 March 2014
                Volume: 25
                Issue: 6
                Pages: 948-964
                Affiliations
                [1] aWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians University, 81377 München, Germany
                [2] cDepartment of Pharmacy, Ludwig-Maximilians University, 81377 München, Germany
                [3] bInstitute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University, 79104 Freiburg, Germany
                [4] dInstitute for Anatomy, University of Duisburg-Essen, 45141 Essen, Germany
                The Hospital for Sick Children
                Author notes
                1Address correspondence to: Ingrid Boekhoff ( ingrid.boekhoff@ 123456lrz.uni-muenchen.de ).
                Article
                Publisher ID: E13-09-0523
                DOI: 10.1091/mbc.E13-09-0523
                PMC ID: 3952862
                PubMed ID: 24451262
                SO-VID: 54db4c58-8a7d-4d02-be1a-ec7555918c2f
                Copyright © © 2014 Arndt et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( http://creativecommons.org/licenses/by-nc-sa/3.0).
                License:

                “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.

                History
                Date received : 10 September 2013
                Date revision received : 13 January 2014
                Date accepted : 15 January 2014
                Categories
                Subject: Articles
                Subject: Signaling
                Series title: A Highlights from MBoC Selection

                ScienceOpen disciplines: Molecular biology
                Data availability:
                ScienceOpen disciplines: Molecular biology

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