Abstract
Suramin and structurally related compounds increase not only the open probability (Po) of ryanodine receptor (RyR) channels but also the single-channel conductance in a unique characteristic manner. In this report, we examine the mechanisms underlying the complex changes to cardiac RyR channel function caused by suramin and the evidence that these changes result from an interaction with calmodulin (CaM) binding sites. In the presence of 100 μM cytosolic Ca2+, we demonstrate that suramin exerts a triphasic effect on Po, indicating the presence of high-, intermediate-, and low-affinity suramin binding sites. The effects of suramin binding to high-affinity sites are Ca2+-dependent; Po is decreased and seems to result from a reduction in the sensitivity of the channel to cytosolic Ca2+. We suggest that this site is the CaM inhibition site. Suramin also binds to intermediate-affinity sites that mediate an increase in Po and an increase in conductance. Cytosolic Ca2+ is not an absolute requirement for the effects mediated via intermediate-affinity suramin sites. The suramin-induced increase in Po and conductance are both concentration-dependent. The correlation between the increase in Po and increase in conductance indicates that the binding events which produce an increase in Po also lead to an increase in conductance and, because the effect is concentration-dependent, multiple suramin molecules must bind to produce the maximum effect. The low-affinity suramin binding sites are inhibition sites and mediate a reduction in Po caused by changes to both open and closed lifetimes.
- Received August 18, 2003.
- Accepted February 4, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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