Osthole or imperatorin-mediated facilitation of glutamate release is associated with a synaptic vesicle mobilization in rat hippocampal glutamatergic nerve endings.
Osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, have previously been shown to facilitate depolarization-evoked glutamate release from rat hippocampal nerve terminals by increasing voltage-dependent Ca(2+) entry. In this study, we further investigated whether osthole and imperatorin possess an action at the exocytotic machinery itself, downstream of a Ca(2+) influx. Our data showed that ionomycin-induced glutamate release and KCl-evoked FM1-43 release were facilitated by osthole and imperatorin, suggesting that some steps after Ca(2+) entry are regulated by these two compounds. Consistent with this, osthole or imperatorin-mediated facilitation of ionomycin-induced glutamate release was occluded by cytochalasin D that inhibits actin polymerization, implying that the disassembly of cytoskeleton is involved. In addition, the facilitatory action of osthole or imperatorin on ionomycin-induced glutamate release was attenuated by the Ca(2+)/calmodulin-dependent kinase II (CaMKII) inhibitor KN62. Furthermore, Western blotting analysis further showed that osthole or imperatorin significantly increased ionomycin-induced phosphorylation of CaMKII and synapsin I, the main presynaptic target of CaMKII. These results suggest, therefore, that osthole or imperatorin-mediated facilitation of glutamate release involves modulation of downstream events controlling synaptic vesicle recruitment and exocytosis, possibly through an increase of CaMKII activation and synapsin I phosphorylation, thereby increasing synaptic vesicle availability for exocytosis.
Lin
Tzu-Yu
TY
Department of Anesthesiology, Far Eastern Memorial Hospital, Pan-Chiao, Taipei, Taiwan 220.
Lu
Cheng-Wei
CW
Huang
Wei-Jan
WJ
Wang
Su-Jane
SJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D015638:Cytochalasin D / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011564:Furocoumarins / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016704:Synapsins / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000502:physiology
D000199:Actins; D002491:Central Nervous System Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D011564:Furocoumarins; D016704:Synapsins; D015638:Cytochalasin D; D018698:Glutamic Acid; D015759:Ionomycin; C063302:KN 62; D011189:Potassium Chloride; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C031534:imperatorin; D002118:Calcium; C046627:osthol