Mechanisms of inhibition of calmodulin-stimulated cyclic nucleotide phosphodiesterase by dihydropyridine calcium antagonists.
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.
Sharma
R K
RK
Department of Medical Biochemistry, University of Calgary, Alberta, Canada.
Wang
J H
JH
Wu
Z
Z
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000494:pharmacology*; D002417:Cattle; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004095:Dihydropyridines / Q000494:pharmacology*; D015736:Felodipine / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008970:Molecular Weight; D009529:Nicardipine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D002147:Calmodulin; D004095:Dihydropyridines; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; C038806:1,4-dihydropyridine; D009529:Nicardipine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015736:Felodipine; D002118:Calcium