Osthole and imperatorin, the active constituents of Cnidium monnieri (L.) Cusson, facilitate glutamate release from rat hippocampal nerve terminals

Su Jane Wang, Tzu Yu Lin, Cheng Wei Lu, Wei Jan Huang

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

We examined the effects of osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, on the release of glutamate from rat hippocampal synaptosomes and investigated the possible mechanism. The results showed that osthole or imperatorin significantly facilitated 4-aminopridine (4-AP)-evoked glutamate release in a concentration-dependent manner. The facilitatory action of osthole or imperatorin was blocked by the vesicular transporter inhibitor bafilomycin A1, not by the glutamate transporter inhibitor l-transpyrrolidine-2,4-dicarboxylic acid (l-trans-PDC), indicating that the release facilitation by osthole or imperatorin results from a enhancement of vesicular exocytosis and not from an increase of Ca2+-independent efflux via glutamate transporter. Examination of the effect of osthole and imperatorin on cytosolic [Ca2+] revealed that the facilitation of glutamate release could be attributed to an increase in voltage-dependent Ca2+ influx. Consistent with this, ω-conotoxin MVIIC, a wide-spectrum blocker of the N- and P/Q-type Ca2+ channels, significantly suppressed the osthole or imperatorin-mediated facilitation of glutamate release, but intracellular Ca2+ release inhibitor dantrolene had no effect. Osthole or imperatorin did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization; thus, the facilitation of 4-AP-evoked Ca2+ influx and glutamate release produced by osthole or imperatorin was not due to it decreasing synaptosomal excitability. In addition, osthole or imperatorin-mediated inhibition of 4-AP-evoked release was prevented by protein kinase C (PKC) inhibitors. Furthermore, osthole or imperatorin increased 4-AP-induced phosphorylation of PKC. Together, these results suggest that osthole or imperatorin effects a facilitation of glutamate release from nerve terminals by positively modulating N-and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC.

Original languageEnglish
Pages (from-to)416-423
Number of pages8
JournalNeurochemistry International
Volume53
Issue number6-8
DOIs
Publication statusPublished - Dec 2008

Fingerprint

Cnidium
Glutamic Acid
Protein Kinase C
Amino Acid Transport System X-AG
osthol
imperatorin
Conotoxins
Dantrolene
Dicarboxylic Acids
Synaptosomes
Protein C Inhibitor
Exocytosis
Protein Kinase Inhibitors
Membrane Potentials

Keywords

  • Erectile function
  • Glutamate exocytosis
  • Hippocampal synaptosomes
  • Imperatorin
  • Osthole
  • PKC
  • Voltage-dependent calcium channels

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Osthole and imperatorin, the active constituents of Cnidium monnieri (L.) Cusson, facilitate glutamate release from rat hippocampal nerve terminals. / Wang, Su Jane; Lin, Tzu Yu; Lu, Cheng Wei; Huang, Wei Jan.

In: Neurochemistry International, Vol. 53, No. 6-8, 12.2008, p. 416-423.

Research output: Contribution to journalArticle

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abstract = "We examined the effects of osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, on the release of glutamate from rat hippocampal synaptosomes and investigated the possible mechanism. The results showed that osthole or imperatorin significantly facilitated 4-aminopridine (4-AP)-evoked glutamate release in a concentration-dependent manner. The facilitatory action of osthole or imperatorin was blocked by the vesicular transporter inhibitor bafilomycin A1, not by the glutamate transporter inhibitor l-transpyrrolidine-2,4-dicarboxylic acid (l-trans-PDC), indicating that the release facilitation by osthole or imperatorin results from a enhancement of vesicular exocytosis and not from an increase of Ca2+-independent efflux via glutamate transporter. Examination of the effect of osthole and imperatorin on cytosolic [Ca2+] revealed that the facilitation of glutamate release could be attributed to an increase in voltage-dependent Ca2+ influx. Consistent with this, ω-conotoxin MVIIC, a wide-spectrum blocker of the N- and P/Q-type Ca2+ channels, significantly suppressed the osthole or imperatorin-mediated facilitation of glutamate release, but intracellular Ca2+ release inhibitor dantrolene had no effect. Osthole or imperatorin did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization; thus, the facilitation of 4-AP-evoked Ca2+ influx and glutamate release produced by osthole or imperatorin was not due to it decreasing synaptosomal excitability. In addition, osthole or imperatorin-mediated inhibition of 4-AP-evoked release was prevented by protein kinase C (PKC) inhibitors. Furthermore, osthole or imperatorin increased 4-AP-induced phosphorylation of PKC. Together, these results suggest that osthole or imperatorin effects a facilitation of glutamate release from nerve terminals by positively modulating N-and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC.",
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AU - Lin, Tzu Yu

AU - Lu, Cheng Wei

AU - Huang, Wei Jan

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N2 - We examined the effects of osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, on the release of glutamate from rat hippocampal synaptosomes and investigated the possible mechanism. The results showed that osthole or imperatorin significantly facilitated 4-aminopridine (4-AP)-evoked glutamate release in a concentration-dependent manner. The facilitatory action of osthole or imperatorin was blocked by the vesicular transporter inhibitor bafilomycin A1, not by the glutamate transporter inhibitor l-transpyrrolidine-2,4-dicarboxylic acid (l-trans-PDC), indicating that the release facilitation by osthole or imperatorin results from a enhancement of vesicular exocytosis and not from an increase of Ca2+-independent efflux via glutamate transporter. Examination of the effect of osthole and imperatorin on cytosolic [Ca2+] revealed that the facilitation of glutamate release could be attributed to an increase in voltage-dependent Ca2+ influx. Consistent with this, ω-conotoxin MVIIC, a wide-spectrum blocker of the N- and P/Q-type Ca2+ channels, significantly suppressed the osthole or imperatorin-mediated facilitation of glutamate release, but intracellular Ca2+ release inhibitor dantrolene had no effect. Osthole or imperatorin did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization; thus, the facilitation of 4-AP-evoked Ca2+ influx and glutamate release produced by osthole or imperatorin was not due to it decreasing synaptosomal excitability. In addition, osthole or imperatorin-mediated inhibition of 4-AP-evoked release was prevented by protein kinase C (PKC) inhibitors. Furthermore, osthole or imperatorin increased 4-AP-induced phosphorylation of PKC. Together, these results suggest that osthole or imperatorin effects a facilitation of glutamate release from nerve terminals by positively modulating N-and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC.

AB - We examined the effects of osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, on the release of glutamate from rat hippocampal synaptosomes and investigated the possible mechanism. The results showed that osthole or imperatorin significantly facilitated 4-aminopridine (4-AP)-evoked glutamate release in a concentration-dependent manner. The facilitatory action of osthole or imperatorin was blocked by the vesicular transporter inhibitor bafilomycin A1, not by the glutamate transporter inhibitor l-transpyrrolidine-2,4-dicarboxylic acid (l-trans-PDC), indicating that the release facilitation by osthole or imperatorin results from a enhancement of vesicular exocytosis and not from an increase of Ca2+-independent efflux via glutamate transporter. Examination of the effect of osthole and imperatorin on cytosolic [Ca2+] revealed that the facilitation of glutamate release could be attributed to an increase in voltage-dependent Ca2+ influx. Consistent with this, ω-conotoxin MVIIC, a wide-spectrum blocker of the N- and P/Q-type Ca2+ channels, significantly suppressed the osthole or imperatorin-mediated facilitation of glutamate release, but intracellular Ca2+ release inhibitor dantrolene had no effect. Osthole or imperatorin did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization; thus, the facilitation of 4-AP-evoked Ca2+ influx and glutamate release produced by osthole or imperatorin was not due to it decreasing synaptosomal excitability. In addition, osthole or imperatorin-mediated inhibition of 4-AP-evoked release was prevented by protein kinase C (PKC) inhibitors. Furthermore, osthole or imperatorin increased 4-AP-induced phosphorylation of PKC. Together, these results suggest that osthole or imperatorin effects a facilitation of glutamate release from nerve terminals by positively modulating N-and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC.

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KW - Imperatorin

KW - Osthole

KW - PKC

KW - Voltage-dependent calcium channels

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