Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.

J Gen Physiol

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.

Published: January 2024

AI Article Synopsis

  • The S4 segment of voltage-sensing domains (VSDs) reacts to electrical voltage by shifting in the electric field, which aids in ion charge movement without allowing physiological ions to pass.
  • Mutations in specific S4 charges can lead to unwanted ionic currents, known as omega currents, which are linked to various diseases affecting cellular excitability.
  • This study reveals that altering a key residue (D129) in the VSD of Ciona intestinalis can create unique anionic omega currents and highlights the significance of countercharge residues in the function of VSDs.

Article Abstract

The S4 segment of voltage-sensing domains (VSDs) directly responds to voltage changes by reorienting within the electric field as a permion. A narrow hydrophobic "gasket" or charge transfer center at the core of most VSDs focuses the electric field into a narrow region and catalyzes the sequential and reversible translocation of S4 positive gating charge residues across the electric field while preventing the permeation of physiological ions. Mutating specific S4 gating charges can cause ionic leak currents through the VSDs. These gating pores or omega currents play important pathophysiological roles in many diseases of excitability. Here, we show that mutating D129, a key countercharge residue in the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP), leads to the generation of unique anionic omega currents. Neutralizing D129 causes a dramatic positive shift of activation, facilitates the formation of a continuous water path through the VSD, and creates a positive electrostatic potential landscape inside the VSD that contributes to its unique anionic selectivity. Increasing the population or dwell time of the conducting state by a high external pH or an engineered Cd2+ bridge markedly increases the current magnitude. Our findings uncover a new role of countercharge residues in the impermeable VSD of Ci-VSP and offer insights into mechanisms of the conduction of anionic omega currents linked to countercharge residue mutations.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686229PMC
http://dx.doi.org/10.1085/jgp.202213311DOI Listing

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