title: Involvement of the cGMP pathway in the osthole-facilitated glutamate release in rat hippocampal nerve endings.
abstract: Osthole, an active constituent isolated from Cnidium monnieri (L.) Cusson, has previously been shown to have the capacity to increase depolarization-evoked glutamate release in rat hippocampal nerve terminals. As cGMP-dependent signaling cascade has been found to modulate glutamate release at the presynaptic level, the aim of this study was to further examine the role of cGMP signaling pathway in the regulation of osthole on glutamate release in hippocampal synaptosomes. Results showed that osthole dose-dependently increased intrasynaptosomal cGMP levels. The elevation of cGMP levels by osthole was prevented by the phosphodiesterase 5 inhibitor sildenafil but was insensitive to the guanylyl cyclase inhibitor ODQ. In addition, osthole-induced facilitation of 4-aminopyridine (4-AP)-evoked glutamate release was completely prevented by the cGMP-dependent protein kinase (PKG) inhibitors, KT5823, and Rp-8-Br-PET-cGMPS. Direct activation of PKG with 8-Br-cGMP or 8-pCPT-cGMP also occluded the osthole-mediated facilitation of 4-AP-evoked glutamate release. Furthermore, sildenafil exhibited a dose-dependent facilitation of 4-AP-evoked release of glutamate and occluded the effect of osthole on the 4-AP-evoked glutamate release. Collectively, our findings suggest that osthole-mediated facilitation of glutamate release involves the activation of cGMP/PKG-dependent pathway.
authors: Department of Anesthesiology, Far Eastern Memorial Hospital, New Taipei City, Taiwan 220.
authors: Tzu Yu
authors: TY
authors: Lin
authors: Cheng Wei
authors: CW
authors: Lu
authors: Wei-Jan
authors: WJ
authors: Huang
authors: Su-Jane
authors: SJ
authors: Wang
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D003374:Coumarins; D013873:Thionucleotides; C073601:KT 5823; C098740:8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate; C016276:8-bromocyclic GMP; D018698:Glutamic Acid; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C046627:osthol