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J. Biol. Chem., Vol. 277, Issue 51, 49167-49174, December 20, 2002

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Suramin Interacts with the Calmodulin Binding Site on the Ryanodine Receptor, RYR1^*

Rao V. L. Papineni, Kristen M. S. O'Connell^§, Hongwei Zhang, Robert T. Dirksen^§, and Susan L. Hamilton^¶

From the  Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030 and ^§ Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Apocalmodulin and Ca²⁺ calmodulin bind to overlapping sites on the ryanodine receptor skeletal form, RYR1, but have opposite functional effects on channel activity. Suramin, a polysulfonated napthylurea, displaces both forms of calmodulin, leading to an inhibition of activity at low Ca²⁺ and an enhancement of activity at high Ca²⁺. Calmodulin binding motifs on RYR1 are also able to directly interact with the carboxy-terminal tail of the transverse tubule dihydropyridine receptor (DHPR) (Sencer, S., Papineni, R. V., Halling, D. B., Pate, P., Krol, J., Zhang, J. Z., and Hamilton, S. L. (2001) J. Biol. Chem. 276, 38237-38241). Suramin binds directly to a peptide that corresponds to the calmodulin binding site of RYR1 (amino acids 3609-3643) and blocks the interaction of this peptide with both calmodulin and the carboxyl-terminal tail of the DHPR ₁-subunit. Suramin, added to the internal solution of voltage-clamped skeletal myotubes, produces a concentration-dependent increase in the maximal magnitude of voltage-gated Ca²⁺ transients without significantly altering L-channel Ca²⁺ channel conducting activity. Together, these results suggest that an interaction between the carboxyl-terminal tail of the DHPR ₁-subunit with the calmodulin binding region of RYR1 serves to limit sarcoplasmic reticulum Ca²⁺ release during excitation-contraction coupling and that suramin-induced potentiation of voltage-gated Ca²⁺ release involves a relief of this inhibitory interaction.

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