DUAL EFFECT OF SURAMIN ON CALCIUM FLUXES ACROSS SARCOPLASMIC-RETICULUM VESICLE MEMBRANES

Suramin is a polysulfonated naphthlyurea developed originally to treat trypanosomiasis. This drug has gained considerable attention recently as an effective anticancer agent. Previous studies have demonstrated that suramin also is an antagonist of ATP at P-2x purinergic receptors . In the present study suramin was shown to evoke Ca++ release from sk eletal muscle sarcoplasmic reticulum (SR) vesicles in a concentration- dependent manner. Ca++ release was inducable from vesicles derived fro m junctional SR but not from those derived from longitudinal SR. This subcellular site-dependent specificity suggests that suramin's actions on muscle involve the Ca++ release channel (CRC), a protein unique to terminal cisternae. This channel has been established as the site of action of ryanoid alkaloids such as ryanodine and dehydroryanodine. Su ramin did not mimic ryanoid actions on the SR CRC, nor did it competit ively diminish ryanodine binding. Instead, suramin actually increased [H-13]ryanodine binding to junctional SR membranes. in this respect, s uramin exhibited agonist effects like those of the adenine nucleotide, beta,gamma-methyleneadenosine 5'-triphosphate. Suramin's mechanism of action did not involve oxidation of sulfhydryl groups on the SR CRC, because dithiothreitol (1 mM) had no effect on suramin-induced Ca++ re lease. Independently of its effects on the CRC, suramin inhibited the Ca++-adenosine triphosphatase (EC 3.6.1.38, SERCA1) of SR membrane ves icles. The ability of suramin to diminish ATP-dependent Ca++ accumulat ion by SR vesicles therefore reflects two distinct actions: 1) activat ion (opening) of the SR Ca++ release channel and 2) inhibition of the Ca++ pump.