Abstract

The influence of luminal and cytoplasmic Ca²⁺ on the ability of ryanodine-sensitive stores to undergo multiple partial (“quantal”) releases has been assessed. Increased luminal Ca²⁺ levels do indeed modulate sarcoplasmic reticulum Ca²⁺ release by lowering the threshold agonist concentration required to elicit release, but the decrease in luminal Ca²⁺ that accompanies a partial release is not sufficient by itself to terminate release. Similarly, an increase in cytoplasmic Ca²⁺ lowers the threshold agonist concentration required to elicit release; thus, the bulk cytoplasmic Ca²⁺ levels attained during a release would only stimulate further release, not terminate it before it reached completion. Very high cytoplasmic Ca²⁺ levels (1–3 mm) also triggered release but were unable to terminate release before reaching completion. Thus, even the high local cytoplasmic Ca²⁺ concentration that might accompany release would also not terminate release. It is concluded that Ca²⁺ feedback can modulate release through ryanodine receptors but that it does not account for the properties of quantal release. The low affinity inhibitor tetracaine induces a decrease in the extent of release that cannot be explained solely by heterogeneous caffeine sensitivity of the stores. The results are interpreted in terms of a scheme that includes (i) heterogeneous sensitivity of stores, conferred in part by differences in luminal Ca²⁺ content and (ii) adaptive behavior on the part of individual ryanodine receptors.