The form and function of channelrhodopsin

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Science  15 Sep 2017:
Vol. 357, Issue 6356, eaan5544
DOI: 10.1126/science.aan5544

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From biophysics to neuroscience tools

The channelrhodopsins and their distinctive light-activated ion channels have emerged as major tools in modern biological research. Deisseroth and Hegemann review the structural and functional properties of these protein photoreceptors. Mutagenesis and modeling studies, coupled with the reintroduction of modified channels into living systems, offer a profound understanding of how these channels work. The insights into the underlying basic science provide foundations for developing further applications in biology and medicine.

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Structured Abstract


Channelrhodopsins (ChRs) are naturally occurring light-gated ion channels that are important for allowing motile algal cells to find suitable light levels. In neuroscience, ChRs have become broadly significant for helping to enable the control of specific circuit elements with light (i.e., optogenetics). Research into how sensation, cognition, and behavior arise from neuronal activity dynamics has been enabled by the expression of ChRs, and other members of the microbial opsin family, in specific cells or in specific connections within nervous systems of behaving animals.

Both the unique light-gated channels themselves and opportunities for their biological application have been under intense investigation. The resulting studies of atomic-scale structure-function relationships have led not only to sophisticated understanding of the underlying chemical processes governing these unique seven-transmembrane channels from the plant kingdom, but also (via optogenetics) to the discovery of fundamental neural circuit principles underlying adaptive and maladaptive behavior in animals.


The atomic-scale understanding of light-gated ion channel function has spanned the key processes of activation/deactivation gating, light adaptation, color tuning, and ion selectivity. A ChR crystal structure–derived, molecular dynamics–calculated pore snapshot (top left panel of the figure) summarizes the wide scope of biophysical and biochemical discoveries. Molecular modeling and redesign have created multiple modes of coupling between delivered photons and spikes in an approach that has illuminated basic principles of protein function and also created new tools for optogenetics. In the top right panel of the figure, the top trace shows a photon-spike transduction mode arising from the ChETA mutation, which results in high-speed, high-fidelity single blue flash–single spike coupling. The second trace shows red photon-spike transduction arising from a redshifted ChR found in nature and then engineered for stronger, more redshifted performance (C1V1). The third trace shows bistable excitation photon-spike logic, in which step-function opsin (SFO) mutations were introduced to create stalled photocycles, allowing stable excitation without continuous light delivery. The bottom trace shows bistable inhibition photon-spike logic; ChRs that are normally cation-conducting, and are therefore excitatory in neural systems, were converted to anion-conducting (inhibitory) ChRs by replacing negatively charged pore residues, followed by SFO mutations for bistability. The C1V1 and SFO designs together allowed us to determine that the medial prefrontal neocortex modulates interactions between two distant subcortical structures to control reward-mediating physiology and behavior (;


The ChR light-gated pore will continue to be studied for its own elegant properties, which are paradigmatic among ion channels because light-gated systems allow structure-function analysis on the femtosecond time scale. Meanwhile, psychiatry has already yielded some of its deepest mysteries to ChR pore structural insights, including in explorations of clinically relevant behavioral states such as anhedonia. Many more opportunities for ChRs in basic neuroscience remain untapped, with the potential for precision redesign to achieve new applications and new roles integrated with other advanced technologies.

A light-gated ion pore.

(Top) Left: Inner workings of channelrhodopsin. Right: New photon-spike transduction modes arising from structure-guided redesign. (Bottom) Discovering the causal underpinnings of depression-related symptomatology. Brain region–specific activity dynamics of the mammalian dopamine neuron–driven reward state (left) are suppressed by the prefrontal cortex (right) as shown, using the second and third photon-spike transduction modes.


Channelrhodopsins are light-gated ion channels that, via regulation of flagellar function, enable single-celled motile algae to seek ambient light conditions suitable for photosynthesis and survival. These plant behavioral responses were initially investigated more than 150 years ago. Recently, major principles of function for light-gated ion channels have been elucidated by creating channelrhodopsins with kinetics that are accelerated or slowed over orders of magnitude, by discovering and designing channelrhodopsins with altered spectral properties, by solving the high-resolution channelrhodopsin crystal structure, and by structural model–guided redesign of channelrhodopsins for altered ion selectivity. Each of these discoveries not only revealed basic principles governing the operation of light-gated ion channels, but also enabled the creation of new proteins for illuminating, via optogenetics, the fundamentals of brain function.

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