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      Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by β-Adrenergic Stimulation*


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          Background: Initial studies on cardiac NAADP signaling were published, but no role for NAADP in cardiac arrhythmias has been reported.

          Results: NAADP affects spontaneous diastolic Ca 2+ transients in cardiac myocytes and arrhythmias in awake mice.

          Conclusion: Results indicate a pivotal role for NAADP in fine-tuning of cardiac excitation-contraction coupling.

          Significance: First evidence is reported for involvement of NAADP in cardiac arrhythmias evoked by β-adrenergic stimulation.


          Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca 2+-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca 2+ release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca 2+ signals sensitive to inhibitors of both acidic Ca 2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca 2+ transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca 2+ transients were recorded both as increases of the free cytosolic Ca 2+ concentration and as decreases of the sarcoplasmic luminal Ca 2+ concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca 2+ transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy.

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          Most cited references45

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          NAADP mobilizes calcium from acidic organelles through two-pore channels

          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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            Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts.

            The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.
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              TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes.

              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.

                Author and article information

                J Biol Chem
                J. Biol. Chem
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                31 May 2013
                5 April 2013
                5 April 2013
                : 288
                : 22
                : 16017-16030
                From the Calcium Signalling Group, Departments of [a ]Biochemistry and Signal Transduction,
                [b ]Cellular and Integrative Physiology,
                [e ]General and Interventional Cardiology,
                [f ]Medical Biometry and Epidemiology,
                [g ]Experimental Pharmacology and Toxicology, and
                [j ]Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany,
                the [c ]Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom,
                the [d ]Institute of Pharmacology, Centre for Physiology and Pharmacology, Medical University Vienna, 1090 Vienna, Austria,
                [h ]Inserm U974, Paris F-75013, France, and
                the [i ]University Pierre et Marie Curie-Paris 6, UMR-S974, CNRS UMR7215, Institut de Myologie, IFR14, F-75013 Paris, France
                Author notes
                [5 ] To whom correspondence should be addressed: The Calcium Signalling Group, Dept. of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: 49-40-7410-52828; Fax: 49-40-7410-56818; E-mail: guse@ 123456uke.de .

                Both authors contributed equally to this work.


                Present address: Integrated Research and Treatment Centre Transplantation, IFB-Tx, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.


                Present address: Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, 5092 Cologne, Germany .


                Present address: Stockholm Centre for Biomembrane Research, Dept. of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.

                © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

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                Signal Transduction

                calcium,calcium intracellular release,naadp,ryanodine receptor,signal transduction
                calcium, calcium intracellular release, naadp, ryanodine receptor, signal transduction


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