January 1999, Volume 126, Issue 1, Pages 251 - 263

Original Article

Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis Sylvie Diochot, Milou-Daniel Drici, Danielle Moinier, Michel Fink & Michel Lazdunski1 Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France     1Author for correspondence

Keywords

Spider toxins;   voltage-gated potassium channels;   Ito;   Kv4 channels;   A-type current;   electrocardiogram

Abstract

1   In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29 - 31 amino acids), which potently block A-type potassium currents, have been purified from the venom of the tarantula Phrixotrichus auratus. 2   Phrixotoxins specifically block Kv4.3 and Kv4.2 currents that underlie Ito1, with an 5<IC50<70 nM, by altering the gating properties of these channels. 3   Neither are the Shaker (Kv1), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear specific of the Shal (Kv4) subfamily of currents and also block Ito1 in isolated murine cardiomyocytes. 4   In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and different degrees of atrio-ventricular 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±8 ms (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 Ito1 that will enable further studies of Kv4.2 and Kv4.3 channel and/or Ito1 expression.

Received 8 August 1998; Revised 1 October 1998; Accepted 9 October 1998

^© Macmillan Publishers Ltd 1999