Key result
NAADP pathway ablation suppresses sinoatrial node beating rate response to β-adrenergic stimulation in animal models.
Why the study?
The role of lysosomal Ca2+ signals in pacemaker activity of the sinoatrial node and in atrial myocardium had not been investigated.
Demonstrates that lysosomal calcium signaling via the NAADP pathway contributes to pacemaker activity and cAMP regulation, providing new mechanistic insights into heart rhythm control and atrial fibrillation.
NAADP pathway may modulate SAN pacemaker activity; leaves open therapeutic relevance pending human validation.
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.
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Akerman et al. (2026) studied Atrial fibrillation and heart rhythm regulation. Pharmacological or genetic ablation of the NAADP pathway was evaluated on Spontaneous beating rate response to β-adrenergic stimulation and cAMP production. Pharmacological or genetic ablation of the NAADP pathway inhibited the spontaneous beating rate response to β-adrenergic stimulation in intact sinoatrial nodes in mouse and goat models.
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