Ryanodine: antithetical calcium channel effects in skeletal muscle sarcoplasmic reticulum

The effects of ryanodine, a neutral alkaloid, on the Ca++ uptake and Ca++ release properties of a skeletal muscle isolated sarcoplasmic reticulum (SR) preparation were evaluated. Ryanodine had no effect on the rate of oxalate-facilitated Ca++ uptake in this SR. Ruthenium red, which reportedly blocks Ca++ channels, increased Ca++ uptake by 2-fold in the SR. Although no effect of ryanodine on Ca++ transport by SR was observed, notable effects on Ca++-induced Ca++ release pathways were discovered. Ryanodine acts on the same Ca++ channels that are affected by ruthenium red. When these Ca++ channels were activated by Ca++ to an open state in the presence of ryanodine, then ryanodine maintained the channel in an activated, open state. However, once Ca++ was taken up by the SR, ryanodine tended to lock the channel in a closed state, producing a condition refractory to Ca++-induced Ca++ release. Thus, dual, opposing effects of ryanodine were demonstrated. In a fast-reaction kinetics measurement of Ca++-induced Ca++ release, both rate and amount of Ca++ release were reduced by ryanodine, and Ca++ appeared to act in a noncompetitive, antagonistic mode. These unusual, antithetical effects of ryanodine on the Ca++ efflux pathway are not mechanistically defined by this study, but they reveal the potential value of ryanodine as a probe for exploring Ca++ channel function.