Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs

Martin Hohenegger, Marina Matyash, Kati Poussu, Annegret Herrmann-Frank, S. Sárközi, Frank Lehmann-Horn, Michael Freissmuth

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Abstract

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 = ~60 μM) > NF037 (EC50 = ~150 μM) > 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 [α- 32P]ATP or after in situ oxidation of [γ-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.

Original languageEnglish
Pages (from-to)1443-1453
Number of pages11
JournalMolecular Pharmacology
Volume50
Issue number6
Publication statusPublished - Dec 1996

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Suramin
Ryanodine Receptor Calcium Release Channel
Skeletal Muscle
Ryanodine
Adenosine Triphosphate
Adenine Nucleotides
Binding Sites
Purinergic P2 Receptors
Sarcoplasmic Reticulum

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hohenegger, M., Matyash, M., Poussu, K., Herrmann-Frank, A., Sárközi, S., Lehmann-Horn, F., & Freissmuth, M. (1996). Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs. Molecular Pharmacology, 50(6), 1443-1453.

Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs. / Hohenegger, Martin; Matyash, Marina; Poussu, Kati; Herrmann-Frank, Annegret; Sárközi, S.; Lehmann-Horn, Frank; Freissmuth, Michael.

In: Molecular Pharmacology, Vol. 50, No. 6, 12.1996, p. 1443-1453.

Research output: Contribution to journalArticle

Hohenegger, M, Matyash, M, Poussu, K, Herrmann-Frank, A, Sárközi, S, Lehmann-Horn, F & Freissmuth, M 1996, 'Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs', Molecular Pharmacology, vol. 50, no. 6, pp. 1443-1453.
Hohenegger M, Matyash M, Poussu K, Herrmann-Frank A, Sárközi S, Lehmann-Horn F et al. Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs. Molecular Pharmacology. 1996 Dec;50(6):1443-1453.
Hohenegger, Martin ; Matyash, Marina ; Poussu, Kati ; Herrmann-Frank, Annegret ; Sárközi, S. ; Lehmann-Horn, Frank ; Freissmuth, Michael. / Activation of the skeletal muscle ryanodine receptor by suramin and suramin analogs. In: Molecular Pharmacology. 1996 ; Vol. 50, No. 6. pp. 1443-1453.
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