An electrostatic potassium channel opener targeting the final voltage sensor transition

Abstract

Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study, we have localized the site of action for PUFAs on the voltage-gated Shaker K channel by introducing positive charges on the channel surface, which potentiated the PUFA effect. Furthermore, we found that PUFA mainly affects the final voltage sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.

A Limited 4 Å Radial Displacement of the S4-S5 Linker Is Sufficient for Internal Gate Closing in Kv Channels

“…The lipid-induced closed state is likely to resemble the voltage-induced one; membranes composed of DOTAP have been shown to have a very high surface potential (47), suggesting that it exerts a similar electrostatic effect on the voltage sensor as the electric field. This is further supported by the finding that negatively charged polyunsaturated fatty acids develop the opposite effect (conductance-voltage relation (GV) shifted to more negative potentials), which is mainly of electrostatic nature (21,22). Zheng et al (42) also demonstrated that the lipid-and voltage-induced conformations are equivalent.…”

Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1

“…Alternatively, negatively charged amphiphiles, for example, free polyunsaturated fatty acids (PUFAs) can potentially bind to the voltage sensor, modulating the voltage-dependence of Kv channel activation. 10,31 Furthermore, binding of por3 to phospholipid may be attenuated at positive potentials because of its positive charges. This property could well explain the voltage-dependence of Kv channel block by por3.…”

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

“…Kv channels are known to first undergo a series of relatively voltage sensitive steps and then a less voltage sensitive opening step when activated. Using a quantitative model of a Shaker Kv channel (53) we can show that if the construction of a chimera is assumed to selectively affect a transition step (by shifting the midpoint of the transition voltage function along the voltage axis), and that Sr 2þ is assumed to selectively affect another transition step (by shifting the midpoint), the Sr 2þ -induced shift of the G(V) curve decreases with increasing V 1/2 in accordance with the experimental results. However, the G(V) curve is also systematically steeper at higher V 1/2 .…”