Emily Akerman, Rebecca A Capel, Eva A Rog-Zielinska, Annika Winbo, Daniel Aston, Florian Falter, Razik Bin Abdul Mu-U-Min, Matthew J Read, Samuel J Bose, Pawel Swietach, Jingyu Wang, Alexander D Corbett, Andreas Koschinski, Serena Calamaio, Dario Melgari, Rachele Prevostini, Ilaria Rivolta, Thamali Ayagama, Ifan Jenkin, Jillian N Simon, Funsho E Fakuade, Julius R Pronto, Parveen Sharma, Charlotte Melia, Qianqian Song, Martin J Booth, Frances M Platt, Ming Lei, Svenja Hester, Roman Fischer, Niels Voigt, Ulrich Schotten, Sander Verheule, Aiswarya Dev, Marie Held, Thomas Waring, Antony Galione, Marco Keller, Franz Bracher, Manuela Zaccolo, Derek A Terrar, Rebecca A B Burton
Our findings support the hypothesis that lysosomal Ca2+ signaling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.
AIMS: In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum (SR) Ca2+ sequestration, producing larger Ca2+ transients. However, the role of lysosomal Ca2+ signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated.
METHODS AND RESULTS: Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signaling microdomains between lysosomes and neighboring SR or mitochondria in mouse, and goat tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3'-5'-cyclic adenosine monophosphate (cAMP) in response to lysosomal signaling, adding a novel trigger for cyclic nucleotide signaling.
CONCLUSIONS: Our findings support the hypothesis that lysosomal Ca2+ signaling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.