Anions that potentiate excitation-contraction coupling may mimic effect of phosphate on Ca²⁺ release channel

Perchlorate is one of a group of inorganic anions that potentiate excitation-contraction coupling in skeletal muscle. We have compared the effect of perchlorate on the sarcoplasmic reticulum (SR) Ca²⁺-release channel with the effect of inorganic phosphate (P(i)), an anion which accumulates in skeletal muscle during exercise. Perchlorate and P(i) (10-20 mM) stimulated Ca²⁺ release from SR vesicles 2- to 3-fold, respectively, and increased ryanodine binding to SR vesicles 1.5-fold. Stimulation of SR Ca²⁺-release channel activity by both perchlorate and P(i) was maximal in the presence of micromolar Ca²⁺ and was associated with an increased affinity of the channel for ryanodine. Other anions known to potentiate muscle contraction (thiocyanate, iodide, and nitrate) also stimulated skeletal muscle SR Ca²⁺ release and ryanodine binding, as did the P(i) analogue vanadate. However, none of the inorganic anions examined altered ryanodine binding to cardiac muscle SR. These results confirm that the SR Ca²⁺-release channel may be a primary site at which perchlorate and other potentiating anions affect skeletal muscle excitation-contraction coupling. In addition, these results demonstrate that the action of these anions on the SR Ca²⁺-release channel resembles that of P(i), a potential endogenous regulator of this channel.