Dual effect of suramin on calcium fluxes across sarcoplasmic reticulum vesicle membranes.
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.
Emmick
J T
JT
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis.
Kwon
S
S
Bidasee
K R
KR
Besch
K T
KT
Besch
H R
HR
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004229:Dithiothreitol / Q000494:pharmacology; D004347:Drug Interactions; D066298:In Vitro Techniques; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology*
D015220:Calcium Channels; D012433:Ryanodine; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D013498:Suramin; D000255:Adenosine Triphosphate; D000252:Calcium-Transporting ATPases; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D002118:Calcium; D004229:Dithiothreitol