Molecular Basis for Time Dependent Modulation of Kv3.1 Channels that Assures Action Potential Repolarization

Abstract

Voltage-dependent potassium (Kv) channels constitute the cell's repolarizing power and shape the action potential (AP) duration. Excitable cells can choose from a large pool of Kv channels, each with different biophysical properties, and tune their AP shape by expressing a selected subset. Kv3 channels have been linked to high-frequency AP firing because of their high threshold of channel opening (around 0 mV) and fast closure kinetics during repolarizing potentials. However, although fast closure prevents the membrane from being excessively repolarized (affecting the next AP generation), it may result in incomplete membrane repolarization. Previously we determined that Shaker-type Kv1 channels display voltage-sensor relaxation, a process that results in slower channel closure. To investigate the relaxation process in Kv3.1, we recorded gating currents from Kv3.1 channels expressed in Xenopus Oocytes. In contrast to Shaker-type Kv1 channels, the relaxation process is in Kv3.1 very fast and the voltage-sensor gets stabilized in the “up” conformation even before channel opening. This behavior might originate in Kv3.1's particular gating kinetics that are characterized by a very steep voltage-dependency. Consequently, Kv3.1 channels actually close slowly (compared to channel opening) in the voltage range between −30 and 0 mV. Furthermore, upon short depolarizations they display a previously uncharacterized hooked tail current during subsequent membrane repolarization. This hooked tail was not linked to an underlying inactivated state and can be simulated with a kinetic model. A hooked tail current yields a temporal increase in repolarizing power that most likely secures membrane repolarization during the falling phase of the AP that normally works as a negative feedback mechanism on channel closure. Therefore, this time dependent modulation of Kv3.1 channel closure is expected to be physiologically important for high-frequency AP firing (Support: NIH-GM030376 and FWO-G043312.N)