Browsing by Author "Brustovetsky, Nikolay"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    β4 Peptide Mediated Voltage-gated Sodium Channel Resurgent Currents of Human Nav1.5 Sodium Channel Expressed in Hek293 Cells Increase after Exposure to Pyrethroid Insecticides Permethrin and Cypermethrin
    (2018-08) Jackson, James O., II; Cummins, Theodore R.; Brustovetsky, Nikolay; Obukhov, Alexander; Sheets, Patrick L.
    Voltage-gated sodium channels (VGSCs) are transmembrane proteins responsible for the initiation of action potentials in excitable tissues by selectively allowing sodium ions (Na+) to flow through the cell membrane. VGSC resurgent currents occur when an open channel blocker from the β4 subunit interacts with the α subunit, transiently blocking the movement of Na+ across the membrane. VGSC subtype Nav1.5 channels are expressed in cardiac tissue and irregularities in their activity can lead to pathophysiological conditions like arrhythmias that can lead to death. Pyrethroid insecticides have been used widely in agriculture, vector control and households around the world for decades and since this is the case, human exposure to these products has increased dramatically. It is important to understand the effects of these insecticides on humans, including how these insecticides affect the heart. This thesis highlights the effects of pyrethroids on β4 peptide mediated Nav1.5 VGSC resurgent currents. The aims of this thesis were to 1) determine Nav1.5 channel activity and if activity changes with exposure to the vehicle (DMSO) used to dilute pyrethroids; 2) investigate the β4 peptide’s effect on these Nav1.5 currents and if resurgent currents are produced; 3) investigate Nav1.5 channel activity when exposed to pyrethroids; and 4) investigate β4 peptide mediated VGSC resurgent current activity after exposure to pyrethroids. Standard whole-cell electrophysiology was used to determine electrophysiological and pharmacological properties of WT Nav1.5 currents. Results from these experiments showed that 1) Nav1.5 channel activity follows established understanding of VGSC: when depolarized a rapid and transient inward current is produced followed by a rapid inactivation; 2) DMSO did not affect activation and inactivation pattern; 3) the β4 peptide produced resurgent currents in Nav1.5; 4) pyrethroids alter electrophysiological properties of Nav1.5 by prolonging inactivation; and 5) β4 peptide mediated resurgent currents are larger after exposure to pyrethroids. Overall, this thesis answers important questions regarding effects of pyrethroids on the cardiac VGSC and has implications for effects on health and highlights the necessity to be mindful of how pyrethroids are used in the future.