Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Itoj in cardiac electrogenesis

Abstract

1 In the present study, two new peptides, phrixotoxins PaTxl and PaTx2 (29-31 amino acids), which potently block A-type potassium currents, have been purified from the venom of the tarantula Phrixotrichits aiiratus. 2 Phrixotoxins specifically block Kv4.3 and Kv4.2 currents that underlie with an 5 IC50 70 nM, by altering the gating properties of these channels. 3 Neither are the Shaker (Kvl), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQTl/IsK, inhibited by phrixotoxins which appear specific of the Shal (Kv4) subfamily of currents and also block in isolated murine cardiomyocytes. 4 In order to evaluate the physiological consequences of the Itol inhibition, mice were injected intravenously with PaTxl, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and different degrees of atrioventricular block. 5 The analysis of the mouse electrocardiogram showed a dose-dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249+11 to 265 ±8ms (P<0.05). 6 It was concluded that phrixotoxins, are new and specific blockers of Kv4.3 and Kv4.2 potassium currents, and hence of / that will enable further studies of Kv4.2 and Kv4.3 channel and/or / expression. © 1999 Stockton Press All rights reserved.