Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of I to1 in cardiac electrogenesis (original) (raw)

1999, British Journal of Pharmacology

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 puri®ed from the venom of the tarantula Phrixotrichus auratus. 2 Phrixotoxins speci®cally block Kv4.3 and Kv4.2 currents that underlie I to1 , with an 55IC 50 570 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 speci®c of the Shal (Kv4) subfamily of currents and also block I to1 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 dierent 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+8 ms (P50.05). 6 It was concluded that phrixotoxins, are new and speci®c blockers of Kv4.3 and Kv4.2 potassium currents, and hence of I to1 that will enable further studies of Kv4.2 and Kv4.3 channel and/or I to1 expression.