Suramin interacts with the calmodulin binding site on the ryanodine receptor, RYR1

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 alpha(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 alpha-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.