Caffeine chelates calcium in the lumen of the endoplasmic reticulum

Abstract

Cytosolic Ca2+ signals are often amplified by massive calcium release from the endoplasmic reticulum (ER). This calcium-induced calcium release (CICR) occurs by activation of an ER Ca2+ channel, the ryanodine receptor (RyR), which is facilitated by both cytosolic- and ER Ca2+ levels. Caffeine sensitizes RyR to Ca2+ and promotes ER Ca2+ release at basal cytosolic Ca2+ levels. This outcome is frequently used as a readout for the presence of CICR. By monitoring ER luminal Ca2+ with the low-affinity genetic Ca2+ probe erGAP3, we find here that application of 50 mM caffeine rapidly reduces the Ca2+ content of the ER in HeLa cells by ∼50%. Interestingly, this apparent ER Ca2+ release does not go along with the expected cytosolic Ca2+ increase. These results can be explained by Ca2+ chelation by caffeine inside the ER. Ca2+-overloaded mitochondria also display a drop of the matrix Ca2+ concentration upon caffeine addition. In contrast, in the cytosol, with a low free Ca2+ concentration (10−7 M), no chelation is observed. Expression of RyR3 sensitizes the responses to caffeine with effects both in the ER (increase in Ca2+ release) and in the cytosol (increase in Ca2+ peak) at low caffeine concentrations (0.3–1 mM) that have no effects in control cells. Our results illustrate the fact that simultaneous monitoring of both cytosolic- and ER Ca2+ are necessary to understand the action of caffeine and raise concerns against the use of high concentrations of caffeine as a readout of the presence of CICR.

The Beneficial Roles of SIRT1 in Drug-Induced Liver Injury

“…Disruption of the Ca 2+ pool activates calpain in the cytosol and converts procaspase-12 to caspase-12 thus activating caspase-9 and caspase-3 to approach apoptosis [121]. On the other hand, the released Ca 2+ is taken up by mitochondria, leading to collapse of inner membrane potential and subsequently the initiation of apoptosis [122]. On the other hand, in the extrinsic pathway, IRE forms the complex with TNF receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) to activate JNK [123].…”

Acute caffeine and capsaicin supplementation and performance in resistance training

“…Previous studies have shown positive results in caffeine supplementation and resistance training for specific training protocols 1,9 . Salatto et al 10 found a significant positive effect of 800 mg of caffeine supplementation in the number of maximum repetitions (NMR) at the bench press and barbell press, both at 80% of one-repetition maximum (1RM).…”

“…Caffeine is an antagonist of the adenosine nucleoside, blocking adenosine receptors, increasing alertness, and reducing fatigue 4 . Another possible mechanism responsible for improving performance is the interaction between caffeine and ryanodine receptors, present in the sarcoplasmic reticulum, which can increase the release of calcium ions in the sarcoplasm 9 . This can contribute to greater interaction between actin and myosin filaments, generating greater strength production 2 .…”

Caffeine and bronchopulmonary dysplasia: Clinical benefits and the mechanisms involved

“…24 Moreover, it has been found that caffeine regulates the reduction of Ca 2+ in the endoplasmic reticulum (ER) and increases cytoplasmic Ca 2+ by binding to RyR. 47 By regulating Ca 2+ levels in the cytoplasm of smooth muscle cells in the human ductus arteriosus, it is possible to regulate the functional closure of PDA. 48 It is speculated that caffeine may reduce PDA requiring treatment by regulating the levels of Ca 2+ in the cytoplasm via the RyR, thereby reducing the occurrence of BPD (Figure 1).…”

“…Some scholars have suggested that caffeine may exert activity as a prostaglandin antagonist; this may be a mechanism for reducing PDA that requires treatment 24 . Moreover, it has been found that caffeine regulates the reduction of Ca 2+ in the endoplasmic reticulum (ER) and increases cytoplasmic Ca 2+ by binding to RyR 47 . By regulating Ca 2+ levels in the cytoplasm of smooth muscle cells in the human ductus arteriosus, it is possible to regulate the functional closure of PDA 48 .…”