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Structure-Guided Transformation of Channelrhodopsin into a Light-Activated Chloride Channel

Science  25 Apr 2014:
Vol. 344, Issue 6182, pp. 420-424
DOI: 10.1126/science.1252367

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Optogenetic Insights

Mapping functional neural circuits for many behaviors has been almost impossible, so Vogelstein et al. (p. 386, published online 27 March; see the Perspective by O'Leary and Marder) developed a broadly applicable optogenetic method for neuron-behavior mapping and used it to phenotype larval Drosophila and thus developed a reference atlas. As optogenetic experiments become routine in certain fields of neuroscience research, creating even more specialized tools is imperative (see the Perspective by Hayashi). By engineering channelrhodopsin, Wietek et al. (p. 409, published online 27 March) and Berndt et al. (p. 420) created two different light-gated anion channels to block action potential generation during synaptic stimulation or depolarizing current injections. These new tools not only improve understanding of channelrhodopsins but also provide a way to silence cells.

Abstract

Using light to silence electrical activity in targeted cells is a major goal of optogenetics. Available optogenetic proteins that directly move ions to achieve silencing are inefficient, pumping only a single ion per photon across the cell membrane rather than allowing many ions per photon to flow through a channel pore. Building on high-resolution crystal-structure analysis, pore vestibule modeling, and structure-guided protein engineering, we designed and characterized a class of channelrhodopsins (originally cation-conducting) converted into chloride-conducting anion channels. These tools enable fast optical inhibition of action potentials and can be engineered to display step-function kinetics for stable inhibition, outlasting light pulses and for orders-of-magnitude-greater light sensitivity of inhibited cells. The resulting family of proteins defines an approach to more physiological, efficient, and sensitive optogenetic inhibition.

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