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Elife. 2016 May 24;5. pii: e15202. doi: 10.7554/eLife.15202.

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

Author information

1
Departments of Chemistry and Chemical Biology and Physics, Harvard University, Cambridge, United States.
2
Howard Hughes Medical Institute, Harvard University, Cambridge, 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.

KEYWORDS:

biophysics; electrophysiology; high throughput screening; ion channels; neuroscience; none; optogenetics; structural biology

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