Lysosomal signalling pathways influence heart rhythm, and regulate atrial function

Abstract

In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca²⁺) release to augment sarcoplasmic reticulum [1] 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. Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signalling microdomains between lysosomes and neighboring SR or mitochondria in mouse, rabbit, goat, and human atrial tissue. The spatial relationship between lysosomes and other Ca²⁺-handling organelles are altered in goat and human atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3′–5′-cyclic adenosine monophosphate in response to lysosomal signalling, adding a novel trigger for cyclic nucleotide signalling. Our findings support the hypothesis that lysosomal Ca²⁺ signalling directly increases cardiomyocyte cAMP and modulates pacemaker activity.