Grafting voltage and pharmacological sensitivity in potassium channels

Abstract

A classical voltage-gated ion channel consists of four voltage-sensing domains (VSDs). However, the roles of each VSD in the channels remain elusive. We developed a GVTDT (Graft VSD To Dimeric TASK3 channels that lack endogenous VSDs) strategy to produce voltage-gated channels with a reduced number of VSDs. TASK3 channels exhibit a high host tolerance to VSDs of various voltage-gated ion channels without interfering with the intrinsic properties of the TASK3 selectivity filter. The constructed channels, exemplified by the channels grafted with one or two VSDs from Kv7.1 channels, exhibit classical voltage sensitivity, including voltage-dependent opening and closing. Furthermore, the grafted Kv7.1 VSD transfers the potentiation activity of benzbromarone, an activator that acts on the VSDs of the donor channels, to the constructed channels. Our study indicates that one VSD is sufficient to voltage-dependently gate the pore and provides new insight into the roles of VSDs.

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

“…S2 C and D). To test if this result derives from a specificity of C28 to the KCNQ1 VSD, we studied the KTQ and KTV channels, which are comprised of the twopore-domain channel TWIK-related, acid-sensitive K + 3 (TASK3) fused with the KCNQ1 and K V 1.2 VSD, respectively (38). TASK3 itself lacks a VSD so that its opening is not dependent on voltage (39), but Lan et al (38) demonstrated that the fused VSD induces voltage-dependent gating in the KTQ and KTV channels (Fig.…”

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

“…However, we found that, unlike its action on KCNQ1, C28 did not alter voltage dependent activation of the Shaker K + channel (Fig S2C, D). To test if this result derives from a specificity of C28 to the KCNQ1 VSD, we studied the KTQ and KTV channels, which are comprised of the two-pore-domain channel TASK3 fused with the KCNQ1 and KV1.2 VSD, respectively(38). TASK3 itself lacks a VSD so that its opening is not dependent on voltage(39), but Lan et al(38) demonstrated that the fused VSD induces voltage dependent gating in the KTQ and KTV channels (Fig 4A-D).…”

“…To test if this result derives from a specificity of C28 to the KCNQ1 VSD, we studied the KTQ and KTV channels, which are comprised of the two-pore-domain channel TASK3 fused with the KCNQ1 and KV1.2 VSD, respectively(38). TASK3 itself lacks a VSD so that its opening is not dependent on voltage(39), but Lan et al(38) demonstrated that the fused VSD induces voltage dependent gating in the KTQ and KTV channels (Fig 4A-D). We found that C28 shifted voltage dependent activation of the KTQ channel, which is comprised of TASK3 fused with the KCNQ1 VSD, to more negative voltages and suppressed the amplitude of the current (Fig 4A, B).…”

“…No reuse allowed without permission. (38). TASK3 itself lacks a VSD so that its opening is not dependent on voltage(39), but Lan et al (38) demonstrated that the fused VSD induces voltage dependent gating in the KTQ and KTV channels (Fig 4A-D).…”

“…(38). TASK3 itself lacks a VSD so that its opening is not dependent on voltage(39), but Lan et al (38) demonstrated that the fused VSD induces voltage dependent gating in the KTQ and KTV channels (Fig 4A-D). We found that C28 shifted voltage dependent activation of the KTQ channel, which is comprised of TASK3 fused with the KCNQ1 VSD, to more negative voltages and suppressed the amplitude of the current (Fig 4A , B).…”