TY - JOUR T1 - Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1443 LP - 1453 VL - 50 IS - 6 AU - M Hohenegger AU - M Matyash AU - K Poussu AU - A Herrmann-Frank AU - S Sarközi AU - F Lehmann-Horn AU - M Freissmuth Y1 - 1996/12/01 UR - http://molpharm.aspetjournals.org/content/50/6/1443.abstract N2 - Ca2+ release from skeletal muscle sarcoplasmic reticulum is activated by adenine nucleotides and suramin. Because suramin is known to interact with ATP-binding enzymes and ATP receptors (P2-purinergic receptors), the stimulation by suramin has been postulated to occur via the adenine nucleotide-binding site of the ryanodine receptor/Ca2+-release channel. We tested this hypothesis using suramin and the following suramin analogs: NF037, NF018, NF023, and NF007. The suramin analogs stimulate the binding of [3H]ryanodine binding to sarcoplasmic reticulum membranes with the following rank order of potency: suramin (EC50 = approximately 60 microM) > NF037 (EC50 = approximately 150 microM) > NF018 > NF023 > NF007. The suramin-induced stimulation occurs via a myoplasmic binding site on the ryanodine receptor as confirmed by binding experiments and single-channel recordings with the purified protein. This binding site is different than that for ATP, a conclusion that is supported by the following observations: (i) Suramin stimulates the association rate and inhibits the dissociation rate of [3H]ryanodine, whereas ATP analogs increase only the on-rate. (ii) In the presence of suramin but not of ATP analogs, [3H]ryanodine binding is resistant to the inhibitory effect of millimolar Mg2+ and Ca2+. (iii) ATP analogs and suramin have an additive effect on [3H]ryanodine binding. (iv) Affinity labeling of the purified ryanodine receptor with 2',3'-dialdehyde [alpha-32P]ATP or after in situ oxidation of [gamma-32P]ATP is not affected by suramin. Thus, our results show that suramin acts as a direct and potent stimulator of the ryanodine receptor but that this action is mediated via a binding site different from that for adenine nucleotides. ER -