Gradual caffeine-induced Ca2+ release in mouse dorsal root ganglion neurons is controlled by cytoplasmic and luminal Ca2+.

Cytosolic free calcium concentration ([Ca2+]c) was recorded from acutely isolated mouse dorsal root ganglion neurons loaded with Ca(2+)-indicator indo-1. The initiation of intracellular Ca2+ release by low (1-5 mM) caffeine concentrations failed to completely empty the caffeine-sensitive stores; subsequent challenge with higher doses of caffeine produced an additional [Ca2+]c elevation. This indicates a gradual Ca2+ release from caffeine-sensitive stores. The sensitivity of Ca2+ stores to caffeine was strongly influenced by endoplasmic reticulum luminal Ca2+ concentration ([Ca2+]i) as an increase in [Ca2+]i produced by a conditioning depolarization-induced Ca2+ entry, caused a several fold decrease of caffeine EC50. By elevating [Ca2+]c a threshold concentration (about 350 nM) can be reached, at which low doses of caffeine (2-5 mM) produced a regenerative Ca2+ release, that depletes the Ca2+ stores almost completely, indicating that all-or-nothing Ca(2+)-induced Ca2+ release can be generated in nerve cells.