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Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm‐1 scorpion toxin
Author(s) -
Milnes James T,
Dempsey Christopher E,
Ridley John M,
Crociani Olivia,
Arcangeli Annarosa,
Hancox Jules C,
Witchel Harry J
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)00662-8
Subject(s) - herg , blockade , potassium channel , chemistry , potassium channel blocker , patch clamp , depolarization , scorpion toxin , pharmacology , biophysics , heterologous expression , scorpion , recombinant dna , biochemistry , biology , receptor , venom , gene
The scorpion toxin peptide BeKm‐1 was synthesised by fluorenylmethoxycarbonyl solid phase chemistry and folded by air oxidation. The peptide's effects on heterologous human ether‐a‐go‐go ‐related gene potassium current ( I HERG ) in HEK293 cells were assessed using ‘whole‐cell’ patch clamp. Blockade of I HERG by BeKm‐1 was concentration‐dependent, temperature‐dependent, and rapid in onset and reversibility. Blockade also exhibited inverse voltage dependence, inverse dependence on duration of depolarisation, and reverse use‐ and frequency‐dependence. Blockade by BeKm‐1 and recombinant ergtoxin, another scorpion toxin known to block HERG, differed in their recovery from HERG current inactivation elicited by strong depolarisation and in their ability to block HERG when the channels were already activated. We conclude that synthetic BeKm‐1 toxin blocks HERG preferentially through a closed (resting) state channel blockade mechanism, although some open channel blockade also occurs.