Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels

  1. Hongkang Zhang
  2. Elaine Reichert
  3. Adam E Cohen  Is a corresponding author
  1. Harvard University, United States

Abstract

Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state-dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels.

Article and author information

Author details

  1. Hongkang Zhang

    Departments of Chemistry and Chemical Biology and Physics, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. Elaine Reichert

    Departments of Chemistry and Chemical Biology and Physics, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Adam E Cohen

    Departments of Chemistry and Chemical Biology and Physics, Harvard University, Cambridge, United States
    For correspondence
    cohen@chemistry.harvard.edu
    Competing interests
    Adam E Cohen, A co-founder of Q-State Biosciences.

Reviewing Editor

  1. Indira M Raman, Northwestern University, United States

Publication history

  1. Received: February 12, 2016
  2. Accepted: May 12, 2016
  3. Accepted Manuscript published: May 24, 2016 (version 1)
  4. Version of Record published: June 14, 2016 (version 2)

Copyright

© 2016, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hongkang Zhang
  2. Elaine Reichert
  3. Adam E Cohen
(2016)
Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels
eLife 5:e15202.
https://doi.org/10.7554/eLife.15202
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