PT  - JOURNAL ARTICLE
AU  - Hélène Gautier
AU  - Jacques Auger
AU  - Christian Legros
AU  - Bruno Lapied
TI  - Calcium-Activated Potassium Channels in Insect Pacemaker Neurons as Unexpected Target Site for the Novel Fumigant Dimethyl Disulfide
AID  - 10.1124/jpet.107.128694
DP  - 2008 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 149--159
VI  - 324
IP  - 1
4099  - http://jpet.aspetjournals.org/content/324/1/149.short
4100  - http://jpet.aspetjournals.org/content/324/1/149.full
SO  - J Pharmacol Exp Ther2008 Jan 01; 324
AB  - Dimethyl disulfide (DMDS), a plant-derived insecticide, is a promising fumigant as a substitute for methyl bromide. To further understand the mode of action of DMDS, we examined its effect on cockroach octopaminergic neurosecretory cells, called dorsal unpaired median (DUM) neurons, using whole-cell patch-clamp technique, calcium imaging and antisense oligonucleotide strategy. At low concentration (1 μM), DMDS modified spontaneous regular spike discharge into clear bursting activity associated with a decrease of the amplitude of the afterhyperpolarization. This effect led us to suspect alterations of calcium-activated potassium currents (IKCa) and [Ca2+]i changes. We showed that DMDS reduced amplitudes of both peak transient and sustained components of the total potassium current. IKCa was confirmed as a target of DMDS by using iberiotoxin, cadmium chloride, and pSlo antisense oligonucleotide. In addition, we showed that DMDS induced [Ca2+]i rise in Fura-2-loaded DUM neurons. Using calcium-free solution, and (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxy-phenyl)ethyl]-acetamide (LOE 908) [an inhibitor of transient receptor potential (TRP)γ], we demonstrated that TRPγ initiated calcium influx. By contrast, ω-conotoxin GVIA (an inhibitor of N-type high-voltage-activated calcium channels), did not affect the DMDS-induced [Ca2+]i rise. Finally, the participation of the calcium-induced calcium release mechanism was investigated using thapsigargin, caffeine, and ryanodine. Our study revealed that DMDS-induced elevation in [Ca2+]i modulated IKCa in an unexpected bell-shaped manner via intracellular calcium. In conclusion, DMDS affects multiple targets, which could be an effective way to improve pest control efficacy of fumigation. The American Society for Pharmacology and Experimental Therapeutics