Voltage-sensing mechanism underlying the gating process of two-pore-domain potassium channels.

Abstract

K_{2P} channels are potassium leak channels known to play an essential role in modulating the membrane potential of neurons and glia. Their dysfunction has been associated with a wide range of diseases, including cancer, autoimmune, CNS, cardiovascular and urinary tract disorders, and dysfunction of K^{+} homeostasis. Despite voltage-dependent activity in most K_{2P} channels, no voltage-sensing mechanism or complex similar to that present in voltage-gated potassium channels has been found. Due to the relatively small size of the K_{2P} channel, and based on the data set, the only area that may be used for voltage sensing is the ion conduction pathway. Therefore, to determine whether the voltage-sensing area is located in this area, we checked the change in electric field in that area through physical analyses based on structural biological data. In this study, we showed that a voltage change occurs in the area of the ion conduction pathway in the K_{2P} channel and therefore, also, the electric field changes in this area. We strengthened and created support for this claim through a physical model. The sensitivity to this voltage originates from the movement of three to four ions that cause a significant change in both the voltage and the electric field. Stimuli of different intensities and at different distances from the region of the ion conduction pathway show significant differences in the opening and closing of the channel and move the channel into a leaky state. The closer the stimulus is to the ion conduction path, the more significant the change in the field. This mechanism provides a clue to the location and possible existence of a voltage-sensing complex in the region of the ion conduction pathway of potassium leak channels.