Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Tuesday Speaker Abstracts

NEW INSIGHTS INTO THE MODAL ACTIVITY OF K V 7 CHANNELS Carlos A. Villalba-Galea ; 1 University of the Pacific, Physiology and Pharmacology, Stockton, CA, USA

Potassium-selective, voltage-gated (K V ) channels of the K V 7 family are commonly found in the nervous, cardiovascular, and gastrointestinal systems. K V 7 channels produce discernible currents at the typical cellular resting potential (about -60 mV). This property sets them apart from other K V channels which are typically closed at voltages below -40 mV. This property also makes them critically important in the regulation of electrical excitability in cells. In fact, disrupted K V 7 channel activity can lead to disorders such as long QT syndrome, arrhythmias, multiple epileptic disorders and peripheral nerve hyper-excitability. In general, K V 7 channels contribute to the cell’s basal K + conductance due to their activity at the resting potentials. Therefore, we argue that the stability of their open state is critical for the physiological function of K V 7 channels. To assess open channel stability, we have focused our studies on the deactivation of K V 7 channels. We have found that deactivation becomes slower as K V 7 channels are kept activated under voltage clamp. This indicates that the open K V 7 channel becomes more stable as they remain activated. Noteworthy, the stabilization of the open channel is not caused by strong depolarization. In fact, this occurs even at negative potentials. This strongly suggests that K V 7 channels undergo further rearrangements into a more stable open conformation following activation. We have shown that changes in voltage dependence, deactivation kinetics, and sensitivity to pharmacological agents are correlated with changes in the deactivation rate. We have proposed that, following activation, the open K V 7 channels dwells on a set of states and eventually transitions into a second set of states from which deactivation is slower. Accordingly, K V 7 channels’ behavior have at least two modes of activity. Here, we are showing that modal activity is unaltered by changes in the voltage sensing machinery, suggesting that the pore domain is responsible for modal activity.

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