Pharmacological activation of the ryanodine receptor in Jurkat T‐lymphocytes

Recently, we provided evidence for cyclic adenosine 5′‐diphosphate‐ribose, cADP‐ribose, as a second messenger in Jurkat T‐lymphocytes upon stimulation of the T‐cell receptor/CD3‐ complex (Guse et al ., 1999). cADP‐ribose mobilizes Ca 2+ from an intracellular Ca 2+ store which is sensitive to caffeine and gated by the ryanodine receptor/Ca 2+ release channel. In the present study we investigated the ability of the trypanocidal drug, suramin, to activate the ryanodine receptor of T‐cells. Since suramin cannot permeate the plasma membrane, it was necessary to microinject the drug into Fura‐2 loaded T‐lymphocytes. In a dose dependent manner suramin increased the intracellular Ca 2+ concentration. The dose‐response curve is very steep and calculates for an EC 50 of 7.6±2.9 m M suramin in the injection pipette. Co‐injection of the selective ryanodine receptor inhibitor ruthenium red completely abolished the suramin induced Ca 2+ transient. This finding allows for the conclusion that the IP 3 ‐receptor sensitive Ca 2+ pool is not the primary target of the suramin induced Ca 2+ transient. Furthermore, Ins(1,4,6)PS 3 , an antagonist of the InsP 3 ‐receptor could not suppress the suramin‐induced Ca 2+ signal. The suramin induced Ca 2+ transients declined very slowly; however, in the presence of Ins(1,4,6)PS 3 this decay was accelerated. In addition, suramin did not interact with the cADP‐ribose binding site of the ryanodine receptor of T‐cells. In conclusion, suramin is found to be an agonist for the T‐cell ryanodine receptor as previously found for the cardiac and skeletal muscle isoform. Therefore, suramin can be designated a universal ryanodine receptor agonist.British Journal of Pharmacology (1999) 128 , 1235–1240; doi: 10.1038/sj.bjp.0702935