Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of I-to1 in cardiac electrogenesis

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 I- tol, with an 5<IC50<70 nM, by altering the gating properties of these chann els. 3 Neither are the Shaker (Kv1), Shab (Kv2) and Shaw, (Kv3) subfamilies of c urrents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear speci fic of the Shal (Kv4) subfamily of currents and also block I,,I in isolated murine cardiomyocytes. 4 In order to evaluate the physiological consequences of the Itol inhibitio n, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature v entricular beats, ventricular tachycardia and different degrees of atrioven tricular block. 5 The analysis of the mouse electrocardiogram showed a dose-dependent prolo ngation of the QT interval, chosen as a surrogate marker for their ventricu lar 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 I-tol that will enable further studies of Kv4.2 and Kv4.3 channel and/or I-tol expression.