ArticleThe Journal of biological chemistry2015
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.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 81 citations in OpenAlex.
- Age-related changes in lysosomal abundance in mouse hearts assessed by Lysotracker fluorescence imaging and autophagy gene expression analysis.The international journal of cardiovascular imaging · 2026Article
- Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.bioRxiv : the preprint server for biology · 2026Article
- Calcium Signaling in Cardiac Fibroblasts: Roles in Fibrosis and Therapeutic Implications.Cardiovascular drugs and therapy · 2026Review
- Lysosomal dysfunction in diabetes and diabetic complications.Frontiers in endocrinology · 2026Review
- CaBiomolecules · 2025Review
- Atrial granules as acidic calcium stores in cardiomyocytes.European heart journal open · 2025Article
- Intracellular Membrane Contact Sites in Skeletal Muscle Cells.Membranes · 2025Review
- CaBiophysics reports · 2024Article
- Activation of IPAmerican journal of physiology. Heart and circulatory physiology · 2024Article
- MASTER-NAADP: a membrane permeable precursor of the CaNature communications · 2024Article
- Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation.iScience · 2024Article
- Store-Operated CaJournal of clinical medicine · 2023Review
- Lysosomal calcium loading promotes spontaneous calcium release by potentiating ryanodine receptors.Biophysical journal · 2023Article
- Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal CaPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- NAADP-Mediated CaHandbook of experimental pharmacology · 2023Article
- Characterization of Endo-Lysosomal Cation Channels Using Calcium Imaging.Handbook of experimental pharmacology · 2023Article
- Two-pore channels: going with the flows.Biochemical Society transactions · 2022Article
- Unexpected Motherhood-Triggered Hearing Loss in the Two-Pore Channel (TPC) Mutant Mouse.Biomedicines · 2022Article
- Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases.Expert opinion on therapeutic targets · 2022Article
- The Sarcoplasmic Reticulum of Skeletal Muscle Cells: A Labyrinth of Membrane Contact Sites.Biomolecules · 2022Review
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Ca(2+)-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca(2+) responses in cardiac myocytes from Tpcn2(-/-) mice, unlike myocytes from wild-type (WT) mice. Ca(2+)/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca(2+) transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of β-adrenoreceptor stimulation were reduced in myocytes from Tpcn2(-/-) mice. Increases in amplitude of L-type Ca(2+) currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2(-/-) mice showing no loss of β-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2(-/-) mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute β-adrenoreceptor stimulation. Hearts from Tpcn2(-/-) mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ∼ 25 nm). We propose that Ca(2+)-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in β-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of β-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of β-adrenoceptors to hypertrophy and associated arrhythmias.
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