Inositol 1,4,5-trisphosphate-induced Ca²⁺ release is regulated by cytosolic Ca²⁺ in intact skeletal muscle

Microinjection of inositol 1,4,5-trisphosphate (InsP₃) into intact skeletal muscle fibers isolated from frogs (Rana temporaria) increased resting cytosolic Ca²⁺ concentration ([Ca²⁺](i)) as measured by double-barreled Ca²⁺-selective microelectrodes. In contrast, microinjection of inositol 1-phosphate, inositol 1,4-biphosphate, and inositol 1,4,5,6-tetrakisphosphate did not induce changes in [Ca²⁺](i). Incubation in low-Ca²⁺ solution, or in the presence of L-type Ca²⁺ channel blockers did not affect InsP₃-induced release of cytosolic Ca²⁺. Neither ruthenium red, a blocker of ryanodine receptor Ca²⁺ release channels, nor cytosolic Mg²⁺, a known inhibitor of the Ca²⁺-induced Ca²⁺-release process, modified the InsP₃-induced release of cytosolic Ca²⁺. However, heparin, a blocker of InsP₃ receptors, inhibited InsP₃-induced release of cytosolic Ca²⁺. Also, pretreatment with dantrolene or azumulene, two inhibitors of cytosolic Ca²⁺ release, reduced [Ca²⁺](i), and prevented InsP₃ from inducing release of cytosolic Ca²⁺. Incubation in caffeine or lengthening of the muscle increased [Ca²⁺](i) and enhanced the ability of InsP₃ to induce release of cytosolic Ca²⁺. These results indicate that InsP₃, at physiological concentrations, induces Ca²⁺ release in intact muscle fibers, and suggest that the InsP₃-induced Ca²⁺ release is regulated by [Ca²⁺](i). A Ca²⁺-dependent effect of InsP₃ on cytosolic Ca²⁺ release could be of importance under physiological or pathophysiological conditions associated with alterations in cytosolic Ca²⁺ homeostasis.