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THE PRESENCE OF A B SUBUNIT INCREASES SENSITIVITY OF SODIUM CHANNEL NAV1.3, BUT NOT NAV1.2, TO TYPE II PYRETHROIDS.
Citation:
MEACHAM, C. A., J. WATKINS, AND T. J. SHAFER. THE PRESENCE OF A B SUBUNIT INCREASES SENSITIVITY OF SODIUM CHANNEL NAV1.3, BUT NOT NAV1.2, TO TYPE II PYRETHROIDS. Presented at Society of Toxicology, Charlotte, NC, March 25 - 29, 2007.
Description:
Voltage-sensitive sodium channels (VSSCs) are a primary target of pyrethroid insecticides. VSSCs are comprised of a pore-forming ¿ and auxillary ß subunits, and multiple isoforms of both subunit types exist. The sensitivity of different isoform combinations to pyrethroids has not been well characterized, yet differences in VSSC sensitivity to pyrethroids have been reported in intact neurons. The present experiments examined the influence of the ß subunit on pyrethroid sensitivity of NaV1.2 and NaV1.3 channels. Xenopus laevis oocytes were transfected with rat ¿ (NaV1.2 or NaV1.3) with or without co-transfection with ß3 or ß1 subunit mRNA. Sodium current elicited by a 45 msec step depolarization to -10 mV from a holding potential of -100 mV was recorded using two-electrode voltage clamp techniques. Tetrodotoxin (1 ¿M) blocked peak current and minimal tail current was present upon repolarization. Deltamethrin (DLT) was applied to the oocytes in ND96 buffer and the percentage of pyrethroid-modified channels was determined based on increases in tail current induced by DLT. In the absence of any ß subunit, DLT (10 uM) modified 1.25 and 3.0% of NaV1.2 or NaV1.3 channels, respectively. Co-transfection with either ß1 or ß3 mRNA dramatically increased the sensitivity of NaV1.3, but not NaV1.2 channels to deltamethrin. Upon co-transfection with ß1, DLT (10 uM) modified 2.17% and 8.31% of NaV1.2 and NaV1.3 channels, respectively; while co-transfection with ß3 did not alter DLT modification of NaV1.2 channels (1.92%) but increased modification of NaV1.3 channels (11.71%). Previous investigations have reported significant age-dependent toxicity of DLT, yet the potential toxicodynamic component of this toxicity is unknown. Because expression of NaV1.2 and ß1 subunits predominate in adult central neurons, while expression of NaV1.3 and ß3 subunits predominates in the developing nervous system, the differential sensitivity of channels comprised of these subunit combinations were examined for several pyrethroids (10 ¿M each; n=3-21 oocytes/compound). Type II pyrethroids differentially modified NaV1.3/B3 and NaV1.2/B1 respectively: ß -cyfluthrin (19.75% vs. 1.54%); esfenvalerate (28.36% vs. 2.67%) and fenvalerate (14.55% vs. 1.89%). These results demonstrate that the ß subunit has a significant impact on the sensitivity of NaV1.3, but not NaV1.2 channels, and that NaV1.3/ß3 channels are more sensitive than NaV1.2/ß1 rat sodium channel to Type II pyrethroids when expressed in Xenopus oocytes. (This is an abstract of a proposed presentation and does not necessarily reflect EPA policy).