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

J Neurochem. 1997 Aug;69(2):845-50. doi: 10.1046/j.1471-4159.1997.69020845.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Animals
  • Binding, Competitive
  • Brain / enzymology
  • Calcium / pharmacology
  • Calcium Channel Blockers / pharmacology*
  • Calmodulin / pharmacology*
  • Cattle
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Dihydropyridines / pharmacology*
  • Felodipine / pharmacology
  • Isoenzymes / antagonists & inhibitors*
  • Molecular Weight
  • Nicardipine / pharmacology
  • Phosphodiesterase Inhibitors / pharmacology*

Substances

  • Calcium Channel Blockers
  • Calmodulin
  • Dihydropyridines
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • 1,4-dihydropyridine
  • Nicardipine
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Felodipine
  • Calcium