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NEUROPHARMACOLOGY

Use-Dependent Block of Voltage-Gated Ca_v2.1 Ca²⁺ Channels by Petasins and Eudesmol Isomers

Pharmacognosy (S.H., H.S.) and Pharmacology and Toxicology (A.K., J.S.), Institute of Pharmacy, Innsbruck, Austria; and Center of Biomolecular Sciences Innsbruck (S.H., A.K., H.S., J.S.), University of Innsbruck, Austria

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 Ca²⁺ 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_v2.1 channels expressed in Xenopus laevis oocytes. P. hybridus extract (0.02 mg/ml), petasin, neopetasin, isopetasin, S-petasin, and iso-S-petasin (50 µM) were weak tonic blockers of Ca_v2.1-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_v2.1 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 - and -eudesmol, a comparable use-dependent inhibition was found in addition to a tonic block component. -Eudesmol and petasins accelerated the voltage-dependent inactivation of Ca_v2.1 channels during depolarizations. We demonstrate that S-petasin, iso-S-petasin, and eudesmol are Ca_v2.1 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_v2.1-inhibitory properties of these petasins may contribute to migraine-prophylactic properties described for P. hybridus extracts.

Address correspondence to: Jörg Striessnig, Pharmacology and Toxicology, Institute of Pharmacy, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria. E-mail: joerg.striessnig{at}uibk.ac.at