Suramin is a polysulfonated naphthylurea 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 P2x
purinergic receptors. In the present study
suramin was shown to evoke Ca++ release from skeletal muscle sarcoplasmic reticulum (SR) vesicles in a concentration-dependent manner. Ca++ release was inducable from vesicles derived from 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.
Suramin did not mimic ryanoid actions on the SR CRC, nor did it competitively diminish
ryanodine binding. Instead,
suramin actually increased [3H]
ryanodine binding to junctional SR membranes. In this respect,
suramin 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++ release. Independently of its effects on the CRC,
suramin inhibited the Ca(++)-
adenosine triphosphatase (EC 3.6.1.38, SERCA1) of SR membrane vesicles. The ability of
suramin to diminish
ATP-dependent Ca++ accumulation by SR vesicles therefore reflects two distinct actions: 1) activation (opening) of the SR Ca++ release channel and 2) inhibition of the Ca++ pump.