The phosphodiesterase III inhibitor olprinone inhibits hippocampal glutamate release via a cGMP/PKG pathway.
Olprinone, an inhibitor of cyclic nucleotide phosphodiesterase III, inhibited an increase in intracellular Ca(2+) concentrations for acutely dissociated rat hippocampal pyramidal neurons induced by extracellular high K(+) (35 mM) depolarization. Olprinone (100 microM) significantly reduced spontaneous glutamate release from rat hippocampal slices. Furthermore, olprinone significantly decreased the rate of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (AMPA-mEPSCs) monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was blocked by KT5823, an inhibitor of protein kinase G (PKG), but not by H-89, an inhibitor of protein kinase A (PKA). In the PKA assay using PC-12 cells, olprinone did not activate PKA. Taken together, the results of the present study show that olprinone attenuates intracellular Ca(2+) rise through voltage-sensitive Ca(2+) channels and inhibits presynaptic glutamate release via a cGMP/PKG pathway.
Fujikawa
Hirokazu
H
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Kanno
Takeshi
T
Nagata
Tetsu
T
Nishizaki
Tomoyuki
T
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
D002227:Carbazoles; D007093:Imidazoles; D007546:Isoquinolines; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D018091:Receptors, AMPA; D013449:Sulfonamides; C073601:KT 5823; D018698:Glutamic Acid; C059498:olprinone; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D011188:Potassium; D002118:Calcium