Abstract
BmP02, a short-chain peptide with 28 residues from the venom of Chinese scorpion Buthus martensi Karsch, has been reported to inhibit the transient outward potassium currents (Ito) in rat ventricular muscle cells. However, it remains unclear whether BmP02 modulates the Kv4.2 channel, one of the main contributors to Ito. The present study investigated the effects of BmP02 on Kv4.2 kinetics and its underlying molecular mechanism. The electrophysiological recordings showed that the inactivation of Kv4.2 expressed in HEK293T cells was significantly delayed by BmP02 in a dose-response manner with EC50 of ~850 nM while the peak current, activation and voltage-dependent inactivation of Kv4.2 were not affected. Meanwhile, the recovery from inactivation of Kv4.2 was accelerated and the deactivation was slowed after the application of BmP02. The site-directed mutagenesis combined with computational modelling identified that K347 and K353, located in the turret motif of the Kv4.2, and E4/E5, D20/D21 in BmP02 are key residues to interact with BmP02 through electrostatic force. These findings not only reveal a novel interaction between Kv4.2 channel and its peptidyl modulator, but also provide valuable information for design of highly-selective Kv4.2 modulators.
Highlights
Ion channels, structural pores distributing in excitable as well as non-excitable cells, selectively allow ions to pass through the cell membranes
Kv4.2 and Kv4.3 are major mediators of inhibit the transient outward potassium currents (Ito) or IA in nervous system and heart [3,4], and their blockage or dysfunction is associated with pathologies, including pain, epilepsy, atrial fibrillation and long QT syndrome [5,6,7,8]
Our previous we investigated the modulatory and the underlying molecular mechanism work showed that BmP02 effects could inhibit transient outward potassium current inof acute isolated ventricular myocytes [18], suggesting that Kv4 channels might be the potential targets of BmP02
Summary
Structural pores distributing in excitable as well as non-excitable cells, selectively allow ions to pass through the cell membranes. Potassium channels are the largest subfamily of ion channels, mediating different potassium currents with distinct kinetic properties [1]. The transient outward potassium current (Ito ) with rapid decay, known as the A-type potassium current (IA ), have been observed in most neural cells and cardiac myocytes. The Kv4 family of voltage-gated potassium channels includes three members Kv4.2 and Kv4.3 are major mediators of Ito or IA in nervous system and heart [3,4], and their blockage or dysfunction is associated with pathologies, including pain, epilepsy, atrial fibrillation and long QT syndrome [5,6,7,8]
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