Mechanisms of inhibition of calmodulin-stimulated cyclic nucleotide phosphodiesterase by dihydropyridine calcium antagonists.

R K Sharma, J H Wang, Z Wu

Department of Medical Biochemistry, University of Calgary, Alberta, Canada.

Journal of neurochemistry 1997 Aug

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Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) is one of the key enzymes involved in the complex interaction between the cyclic nucleotide and Ca2+ second-messenger systems. CaMPDE exists as tissue-specific isozymes, and initially these isozymes were designated according to their respective subunit molecular mass. A variety of pharmacological agents have been used to inhibit CaMPDE, and this inhibition occurs mostly via Ca2+-dependent association with the proteins. We have examined the effect of dihydropyridine Ca2+-channel blockers felodipine and nicardipine on CaMPDE. The results suggest that the 63-kDa (PDE 1B1) and 60-kDa (PDE 1A2) CaMPDE isozymes are inhibited by felodipine and nicardipine by partial competitive inhibition and that these two Ca2+ antagonists appear to counteract each other. This study further demonstrates the existence of a specific site, distinct from the active site on CaMPDE, that exhibits high-affinity binding of these drugs. Felodipine and nicardipine have similar affinities for 60-kDa CaMPDE isozymes but bring about different levels of enzyme inhibition, suggesting the possibility of designing specific drugs that can protect the enzyme from inhibition by dihydropyridine Ca2+-channel blockers.

Citation

R K Sharma, J H Wang, Z Wu. Mechanisms of inhibition of calmodulin-stimulated cyclic nucleotide phosphodiesterase by dihydropyridine calcium antagonists. Journal of neurochemistry. 1997 Aug;69(2):845-50