Sphingosylphosphocholine modulates the ryanodine receptor/calcium-release channel of cardiac sarcoplasmic reticulum membranes

Sphingosylphosphocholine (SPC) modulates Ca²⁺ release from isolated cardiac sarcoplasmic reticulum membranes; 50 μM SPC induces the release of 70-80% of the accumulated calcium. SPC releases calcium from cardiac sarcoplasmic reticulum through the ryanodine receptor, since the release is inhibited by the ryanodine receptor channel antagonists ryanodine, Ruthenium Red and sphingosine. In intact cardiac myocytes, even in the absence of extracellular calcium, SPC causes a rise in diastolic Ca²⁺, which is greatly reduced when the sarcoplasmic reticulum is depleted of Ca²⁺ by prior thapsigargin treatment. SPC action on the ryanodine receptor is Ca²⁺-dependent. SPC shifts to the left the Ca²⁺-dependence of [³H]ryanodine binding, but only at high pCa values, suggesting that SPC might increase the sensitivity to calcium of the Ca²⁺-induced Ca²⁺-release mechanism. At high calcium concentrations (pCa 4.0 or lower), where [³H]ryanodine binding is maximally stimulated, no effect of SPC is observed. We conclude that SPC releases calcium from cardiac sarcoplasmic reticulum membranes by activating the ryanodine receptor and possibly another intracellular Ca²⁺-release channel, the sphingolipid Ca²⁺-release-mediating protein of endoplasmic reticulum (SCaMPER), which we have identified for the first time in cardiac tissue.