Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter

Abstract

Mode-shift or hysteresis has been reported in ion channels. Voltageshift for gating currents is well documented for voltage-gated cation channels (VGCC), and it is considered a voltage-sensing domain's (VSD) intrinsic property. However, uncoupling the Shaker K + channel's pore domain (PD) from the VSD prevented the modeshift of the gating currents. Consequently, it was proposed that an open-state stabilization of the PD imposes a mechanical load on the VSD, which causes its mode-shift. Furthermore, the mode-shift displayed by hyperpolarization-gated cation channels is likely caused by structural changes at the channel's PD similar to those underlying C-type inactivation. To demonstrate that the PD of VGCC undergoes hysteresis, it is imperative to study its gating process in the absence of the VSD. A back-door strategy is to use KcsA (a K + channel from the bacteria Streptomyces lividans) as a surrogate because it lacks a VSD and exhibits an activation coupled to C-type inactivation. By directly measuring KcsA's activation gate opening and closing in conditions that promote or halt C-type inactivation, we have found (i) that KcsA undergoes mode-shift of gating when having K + as the permeant ion; (ii) that Cs + or Rb + , known to halt C-inactivation, prevented mode-shift of gating; and (iii) that, in the total absence of C-type inactivation, KcsA's mode-shift was prevented. Finally, our results demonstrate that an allosteric communication causes KcsA's activation gate to "remember" the conformation of the selectivity filter, and hence KcsA requires a different amount of energy for opening than for closing.hysteresis | KcsA | potassium channels | mode-shift | C-type inactivation

Conformational Changes during Potassium-Channel Gating

“…It is known that the VSD communicates with a pore via its linker to the gate, and it is also known that the gate communicates with the selectivity filter 21,63,71 . To our knowledge, there is no previous evidence of communication between the VSD and the pore via the interface between them.…”

“…Some channels rely on large intracellular domains or auxiliary subunits for their correct function. Since the importance and function of the segments in gating varies between channels, it is also likely that the communication between these segments varies, which different studies have confirmed [22][23][24][25][26][27][28]58,60,63,71 .…”

“…The shift in the Q(V) relationship is known as mode-shift, and it indicates a change in the energy landscape during inactivation that forces the charge movement to take an alternative kinetic pathway when S4 returns to a down position. The voltage sensor, therefore, requires stronger repolarization to return to its resting position and close the gate after long depolarization than after short [60][61][62][63] . This could either be due to an increase in the resistance in the downward movement of the voltage-sensor, an increase in resistance to close the internal gate, or both.…”

“…Mode-shift can also be found in the pH-sensitive K channel (KcsA) which lacks VSDs 63 . The mode-shift seems to be an intrinsic property of both the pore and the VSD in these isolated systems.…”

Computational Study on Hysteresis of Ion Channels: Multiple Solutions to Steady-State Poisson-Nernst-Planck Equations

“…Hysteresis phenomenon is ubiquitous in optical devices [16], many-body systems [8], and biological systems [7]. In recent years, there has been a growing interest in understanding hysteretic response of ion channels to varying applied voltages [3,9,14,31,44,48,51,60]. Hysteresis of ions channels is of physiological significance, since it involves many human physiological processes [9,44,60].…”