Mechanisms underlying the complementary roles of NAADP and cADPR in cardiac muscle, including the potential arrhythmogenic effects of these compounds
- 1 January 2013 to 30 November 2013
- Awards: Pump-priming Awards
Our observations show that the Ca2+-mobilising cellular messenger, NAADP, plays unexpected but major roles both in acute beta-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of beta-adrenoceptors to cardiac hypertrophy and associated arrhythmias. These cardiac actions of NAADP involve two pore ion channels (TPC2) at lysosomal/sarcoplasmic reticulum junctions. Generation of NAADP, and the related arrhythmogenic Ca2+-mobilising cellular messenger, cADPR, in the heart were shown to depend on the same enzyme, CD38, and inhibition of this synthetic pathway reduces the ability of beta-adrenoreceptor stimulation both to increase the amplitude of Ca2+ transients and to disturb heart rhythm.
Publications linked to this award:
- Lin WK, Bolton EL, Cortopassi WA, Wang Y, O'Brien F, Maciejewska M, Jacobson MP, Garnham C, Ruas M, Parrington J, Lei M, Sitsapesan R, Galione A, Terrar DA. Synthesis of the Ca2+-mobilizing messengers NAADP and cADPR by intracellular CD38 enzyme in the mouse heart: Role in β-adrenoceptor signaling. J Biol Chem. 2017 Aug 11;292(32):13243-13257. doi: 10.1074/jbc.M117.789347. Epub 2017 May 24.
- Capel RA, Bolton EL, Lin WK, Aston D, Wang Y, Liu W, Wang X, Burton RA, Bloor-Young D, Shade KT, Ruas M, Parrington J, Churchill GC, Lei M, Galione A, Terrar DA. Two-pore channels (TPC2s) and nicotinic acid adenine dinucleotide phosphate (NAADP) at lysosomal-sarcoplasmic reticular junctions contribute to acute and chronic β-adrenoceptor signaling in the heart. J Biol Chem. 2015 Dec 11;290(50):30087-98. doi: 10.1074/jbc.M115.684076. Epub 2015 Oct 5.