ArticleThe Biochemical journal2008
Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor.
Article in The Biochemical journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
96 citing papers in PubMed, 1 synthesis or guideline pooled it, 180 citations in OpenAlex.
- Energy Drinks as the Legal Cocaine? A Comparative Review of Cardiac Physiopathological and Histopathological Patterns.Cardiovascular toxicology · 2025Pooled it
- Pathological calcium overload impairs skeletal muscle regeneration through sustained NFAT-dependent proliferative signaling.Experimental & molecular medicine · 2026Article
- Potassium-Selective Nanoelectrode Arrays for Single-Cell Profiling of Human iPSC-Derived Cardiomyocytes.ACS nano · 2026Article
- Unwanted Clinical Complications Following the Consumption of Death Coffee: A Case Series.Neuropsychopharmacology reports · 2025Article
- Structural insights into transmembrane helix S0 facilitated RyR1 channel gating by CaNature communications · 2025Article
- Effects of Acute Caffeine Ingestion on Physical Performance and Skill Execution in Volleyball Players: A Systematic Review and Meta-Analysis.International journal of exercise science · 2025Article
- The utility of caffeine citrate as a neuroprotectant in the early life of premature newborns: a literature review of the effects on neurodevelopmental outcomes.Frontiers in pediatrics · 2025Review
- The Effects of Caffeine on Blood Platelets and the Cardiovascular System through Adenosine Receptors.International journal of molecular sciences · 2024Review
- Coffee Bean and Its Chemical Constituent Caffeine and Chlorogenic Acid as Promising Chemoprevention Agents: Updated Biological Studies against Cancer Cells.Molecules (Basel, Switzerland) · 2024Review
- A PACAP-activated network for secretion requires coordination of CaMolecular biology of the cell · 2024Article
- Timing Matters: Time of Day Impacts the Ergogenic Effects of Caffeine-A Narrative Review.Nutrients · 2024Review
- Targeting NLRP3 signaling reduces myocarditis-induced arrhythmogenesis and cardiac remodeling.Journal of biomedical science · 2024Article
- Long-Term Alcohol-Activated c-Jun N-terminal Kinase Isoform 2 Preserves Cardiac Function but Drives CaCells · 2023Article
- Alcohol and caffeine synergistically induce spontaneous ventricular tachyarrhythmias: ameliorated with dantrolene treatment.Heart rhythm O2 · 2023Article
- Recent advancements in pharmacological strategies to modulate energy balance for combating obesity.RSC medicinal chemistry · 2023Review
- The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.Redox biology · 2023Article
- Sarcospan Deficiency Increases Oxidative Stress and Arrhythmias in Hearts after Acute Ischemia-Reperfusion Injury.International journal of molecular sciences · 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
- Caffeine for Prevention of Alzheimer's Disease: Is the ABiomolecules · 2023Review
- Cardiorespiratory and Neuroprotective Effects of Caffeine in Neonate Animal Models.Animals : an open access journal from MDPI · 2023Review
36 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Caffeine has long been used as a pharmacological probe for studying RyR (ryanodine receptor)-mediated Ca(2+) release and cardiac arrhythmias. However, the precise mechanism by which caffeine activates RyRs is elusive. In the present study, we investigated the effects of caffeine on spontaneous Ca(2+) release and on the response of single RyR2 (cardiac RyR) channels to luminal or cytosolic Ca(2+). We found that HEK-293 cells (human embryonic kidney cells) expressing RyR2 displayed partial or 'quantal' Ca(2+) release in response to repetitive additions of submaximal concentrations of caffeine. This quantal Ca(2+) release was abolished by ryanodine. Monitoring of endoplasmic reticulum luminal Ca(2+) revealed that caffeine reduced the luminal Ca(2+) threshold at which spontaneous Ca(2+) release occurs. Interestingly, spontaneous Ca(2+) release in the form of Ca(2+) oscillations persisted in the presence of 10 mM caffeine, and was diminished by ryanodine, demonstrating that unlike ryanodine, caffeine, even at high concentrations, does not hold the channel open. At the single-channel level, caffeine markedly reduced the threshold for luminal Ca(2+) activation, but had little effect on the threshold for cytosolic Ca(2+) activation, indicating that the major action of caffeine is to reduce the luminal, but not the cytosolic, Ca(2+) activation threshold. Furthermore, as with caffeine, the clinically relevant, pro-arrhythmic methylxanthines aminophylline and theophylline potentiated luminal Ca(2+) activation of RyR2, and increased the propensity for spontaneous Ca(2+) release, mimicking the effects of disease-linked RyR2 mutations. Collectively, our results demonstrate that caffeine triggers Ca(2+) release by reducing the threshold for luminal Ca(2+) activation of RyR2, and suggest that disease-linked RyR2 mutations and RyR2-interacting pro-arrhythmic agents may share the same arrhythmogenic mechanism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.