Graded or "quantal" Ca2+ release from intracellular stores has been observed in various cell types following activation of either ryanodine receptors (RyR) or inositol 1,4,5-trisphosphate receptors (InsP3R). The mechanism causing the release of Ca2+ stores in direct proportion to the strength of stimulation is unresolved. We investigated the properties of quantal Ca2+ release evoked by activation of RyR in PC12 cells, and in particular whether the sensitivity of RyR to the agonist caffeine was altered by lumenal Ca2+. Quantal Ca2+ release was observed in cells stimulated with 1 to 40 mM caffeine, a range of caffeine concentrations giving a >10-fold change in lumenal Ca2+ content. The Ca2+ load of the caffeine-sensitive stores was modulated by allowing them to refill for varying times after complete discharge with maximal caffeine, or by depolarizing the cells with K+ to enhance their normal steady-state loading. The threshold for RyR activation was sensitized approximately 10-fold as the Ca2+ load increased from a minimal to a maximal loading. In addition, the fraction of Ca2+ released by low caffeine concentrations increased. Our data suggest that RyR are sensitive to lumenal Ca2+ over the full range of Ca2+ loads that can be achieved in an intact PC12 cell, and that changes in RyR sensitivity may be responsible for the termination of Ca2+ release underlying the quantal effect.