Reciprocal regulation of calcium dependent and calcium independent cyclic AMP hydrolysis by protein phosphorylation

J Neurochem. 2002 May;81(3):422-33. doi: 10.1046/j.1471-4159.2002.00903.x.

Abstract

The hydrolysis of cyclic nucleotide second messengers takes place through multiple cyclic nucleotide phosphodiesterases (PDEs). The significance of this diversification is not fully understood. Here we report the differential regulation of low K(m) Ca2+-activated (PDE1C) and Ca2+-independent, rolipram-sensitive (PDE4) PDEs by protein phosphorylation in the neuroendocrine cell line AtT20. Incubation of cells with 8-(4-chlorophenylthio)-cyclic AMP (CPT-cAMP) enhanced PDE4 and reduced PDE1C activity. These effects were blocked by H89 indicating mediation by cAMP-dependent protein kinase (PKA), furthermore in broken cell preparations PKA produced the same reciprocal changes of PDE activities. Calyculin A, an inhibitor of protein phosphatases 1 and 2 A, stimulated PDE4 and enhanced the inhibitory effect of CPT-cAMP on PDE1C. The reduction of PDE1C activity was characterized by a marked attenuation of the activation by Ca2+/calmodulin. Stimulation of PDE4 activity by CPT-cAMP or calyculin A was attributable to PDE4D3 and these effects could also be reproduced in human embryonic kidney cells expressing epitope-tagged PDE4D3. Together, these data show reciprocal regulation of PDE1C and PDE4D by PKA, which represents a novel scheme for plasticity in intracellular signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / chemistry
  • 3',5'-Cyclic-AMP Phosphodiesterases / genetics
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cell Fractionation
  • Cell Line
  • Corticotropin-Releasing Hormone / pharmacology
  • Cyclic AMP / analogs & derivatives*
  • Cyclic AMP / metabolism*
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrolysis
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kidney / cytology
  • Kidney / metabolism
  • Mice
  • Oxazoles / pharmacology
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphorylation / drug effects
  • Pituitary Gland, Anterior / cytology
  • Pituitary Gland, Anterior / drug effects
  • Pituitary Gland, Anterior / metabolism
  • Precipitin Tests
  • Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Second Messenger Systems / physiology
  • Thionucleotides / pharmacology

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Oxazoles
  • Proteins
  • Thionucleotides
  • 8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
  • calyculin A
  • Corticotropin-Releasing Hormone
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoprotein Phosphatases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human
  • Calcium