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Use-Dependent Block of Voltage-Gated Cav2.1 Ca2+Channels by Petasins and Eudesmol Isomers
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 330:220-226
- Publication Year :
- 2009
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2009.
-
Abstract
- Migraine is a frequent and often disabling disease. Treatment is unsatisfactory in many patients. A disturbed dynamic balance between excitatory and inhibitory signal processing with enhanced cortical activity probably underlies common forms of migraine. Presynaptic voltage-gated Ca(2+) channels are critical determinants of neurotransmitter release and also contribute to trigeminovascular signal transduction. Because clinical evidence exists for migraine-prophylactic actions of Petasites hybridus extracts, we investigated whether petasins comprising the main constituents of the extract inhibit currents through presynaptic Ca(v)2.1 channels expressed in Xenopus laevis oocytes. P. hybridus extract (0.02 mg/ml), petasin, neopetasin, isopetasin, S-petasin, and iso-S-petasin (50 microM) were weak tonic blockers of Ca(v)2.1-mediated barium currents (I(Ba)) during infrequent depolarizations (0.1 Hz), but their inhibitory potency increased at higher stimulation rates (1 Hz), indicating preferential block of open and/or inactivated channels. Sulfur-containing compounds (S-petasin, Iso-S-petasin) were the most potent significantly promoting the accumulation of Ca(v)2.1 channel in inactivated states during pulse trains (I(Ba) decrease during 1-Hz pulse trains: control, 45%, S-petasin, 79%; iso-S-petasin, 80%). For the Eucalyptus williamsiania sesquiterpenes alpha- and gamma-eudesmol, a comparable use-dependent inhibition was found in addition to a tonic block component. Alpha-eudesmol and petasins accelerated the voltage-dependent inactivation of Ca(v)2.1 channels during depolarizations. We demonstrate that S-petasin, iso-S-petasin, and eudesmol are Ca(v)2.1 channel inhibitors preferentially acting as use-dependent channel blockers and with the sulfur-containing substituent in position 3 of the petasins serving as important functional feature. The Ca(v)2.1-inhibitory properties of these petasins may contribute to migraine-prophylactic properties described for P. hybridus extracts.
- Subjects :
- Stereochemistry
Petasin
Stimulation
Inhibitory postsynaptic potential
Cav2.1
Tonic (physiology)
Calcium Channels, Q-Type
Xenopus laevis
chemistry.chemical_compound
Calcium Channels, N-Type
Oils, Volatile
Animals
Channel blocker
Pharmacology
biology
Voltage-gated ion channel
Plant Extracts
Calcium Channels, P-Type
Petasites
Calcium Channel Blockers
chemistry
Excitatory postsynaptic potential
biology.protein
Biophysics
Molecular Medicine
Female
Sesquiterpenes
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 330
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....b8093ce306e8d187957f5e2c11065c8b