73 Scopus citations


The voltage-sensing domain of voltage-gated channels is comprised of four transmembrane helices (SI-S4), with conserved positively charged residues in S4 moving across the membrane in response to changes in transmembrane voltage. Although it has been shown that positive charges in S4 interact with negative countercharges in S2 and S3 to facilitate protein maturation, how these electrostatic interactions participate in channel gating remains unclear. We studied a mutation in Kv7.1 (also known as KCNQl or KvLQTl ) channels associated with long QT syndrome (ElK in S2) and found that reversal of the charge at El eliminates macroscopic current without inhibiting protein trafficking to the membrane. Pairing E1R with individual charge reversal mutations of arginines in S4 (Rl-R4) can restore current, demonstrating that R1-R4 interact with E1. After mutating E1 to cysteine, we probed E1C with charged methanethiosulfonate (MTS) reagents. MTS reagents could not modify E1C in the absence of KCNEl. With KCNEl, (2-sulfonatoethyl) MTS (MTSES)" could modiřy E1C, but [2-(trimethylammonium)ethyl] MTS (MTSET)+ could not, confirming the presence of a positively charged environment around E1C that allows approach by MTSES- but repels MTSET+. We could change the local electrostatic environment of ElC by making charge reversal and/or neutralization mutations of R1 and R4, such that MTSET+ modified these constructs depending on activation states of the voltage sensor. Our results confirm the interaction between El and the fourth arginine in S4 (R4) predicted from open-state crystal structures of Kv channels and reveal an El-Rl interaction in the resting state. Thus, E1 engages in electrostatic interactions with arginines in S4 sequentially during the gating movement of S4. These electrostatic interactions contribute energetically to voltage-dependent gating and are important in setting the limits for S4 movement.

Original languageEnglish
Pages (from-to)595-606
Number of pages12
JournalJournal of General Physiology
Issue number6
StatePublished - Jun 2010


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