Dynamic modulation of voltage-dependent Kv7.2-7.3 channel opening by voltage-sensor relaxation


Carlos A. Villalba-Galea: 0000-0002-6489-4651

Document Type


Conference Title/Conference Publication

Biophysical Journal


Biophysical Society 55th Annual Meeting


Baltimore, MD

Conference Dates

March 5-9, 2011

Date of Presentation







3, Supplement 1



First Page



S4-type voltage-sensor (VS) domains are common to voltage-gated ion channels (VGCs) and voltage-sensitive phosphatases (VSPs). In ciVSP, depolarization to +80 mV initially causes VS activation, generating rapid sensing charge (Q) movement. Sustained depolarization subsequently elicits a voltage-independent conformational rearrangement termed relaxation. Because the relaxed state is thermodynamically more stable than the activated state, relaxation causes a negative shift in the Q-V relation. Relaxation may be an intrinsic property of the VS domain because it is observed in the absence of the ciVSP catalytic domain. Since the VS and pore domains are coupled in VGCs, we wondered whether VS relaxation might alter voltage-dependent opening of an ion channel conductance (G). By analogy to ciVSP, we hypothesized that relaxation would shift the G-V relation toward negative potentials. In order to test this hypothesis, we used two-electrode voltage clamp to measure K+ currents in Xenopus oocytes expressing Kv7.2 and Kv7.3 mRNAs. As expected, prolonged depolarizations to +80 mV caused the steady-state G-V relation to shift toward negative potentials, indicating that VS relaxation alters the voltage-dependence of channel opening in heteromeric Kv7.2-7.3 channels. Furthermore, the magnitude of the shift in the midpoint of the G-V relation was found to depend on the duration of the +80 mV prepulse. Similar to ciVSP, the progressive shift in the G-V relation may be interpreted as an index of relaxation and used to measure the rates of entry into and recovery from the relaxed state. Our data therefore imply that the voltage dependence of VGC opening is likely to be dynamically modulated by conformational transitions that are intrinsic to the VS domain in a voltage-gated channel complex. VS relaxation may represent a widespread mechanism for regulating VGC function altering the relative positions of the Q-V and G-V relations.