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 Ca²⁺-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⁺]₁) as an increase in [Ca²⁺]₁ 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 Ca²⁺-induced Ca²⁺ release can be generated in nerve cells.