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

Microinjection of inositol 1,4,5-trisphosphate (InsP ₃) 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 InsP ₃-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 InsP ₃-induced release of cytosolic Ca²⁺. However, heparin, a blocker of InsP ₃ receptors, inhibited InsP ₃-induced release of cytosolic Ca²⁺. Also, pretreatment with dantrolene or azumulene, two inhibitors of cytosolic Ca²⁺ release, reduced [Ca²⁺]_i, and prevented InsP ₃ from inducing release of cytosolic Ca²⁺. Incubation in caffeine or lengthening of the muscle increased [Ca²⁺]_i and enhanced the ability of InsP ₃ to induce release of cytosolic Ca²⁺. These results indicate that InsP ₃, at physiological concentrations, induces Ca²⁺ release in intact muscle fibers, and suggest that the InsP ₃-induced Ca²⁺ release is regulated by [Ca²⁺]_i. A Ca²⁺-dependent effect of InsP ₃ on cytosolic Ca²⁺ release could be of importance under physiological or pathophysiological conditions associated with alterations in cytosolic Ca²⁺ homeostasis. Received: 15 December 1995/Received after revision and accepted: 10 May 1996