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

Version of Record: June 14, 2016
Accepted Manuscript: May 24, 2016

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1. Part of Collection
Ion channels: A Collection of Articles

Edited by Kenton J Swartz et al.

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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.

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Hongkang Zhang

Departments of Chemistry and Chemical Biology and Physics, Harvard University, Cambridge, United States

Competing interests
No competing interests declared.
Elaine Reichert

Departments of Chemistry and Chemical Biology and Physics, Harvard University, Cambridge, United States

Competing interests
No competing interests declared.
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.

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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.