ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers.
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124 citing papers in PubMed, 225 citations in OpenAlex.
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- Bridging Model and Experiment in Systems Neuroscience with Cleo: The Closed-Loop, Electrophysiology, and Optophysiology Simulation Testbed.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
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- VTA dopaminergic neuronal activity during NREM sleep is modulated by learning and facilitates motor memory consolidation.Science advances · 2025Article
- Roadmap for direct and indirect translation of optogenetics into discoveries and therapies for humans.Nature neuroscience · 2025Review
- Bridging model and experiment in systems neuroscience with Cleo: the Closed-Loop, Electrophysiology, and Optophysiology simulation testbed.bioRxiv : the preprint server for biology · 2025Article
- Ion-conducting and gating molecular mechanisms of channelrhodopsin revealed by true-atomic-resolution structures of open and closed states.Nature structural & molecular biology · 2025Article
- Role of Hypothalamic CRH Neurons in Regulating the Impact of Stress on Memory and Sleep.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
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- A hypothalamic circuit mechanism underlying the impact of stress on memory and sleep.bioRxiv : the preprint server for biology · 2024Article
- Parallel photocycle kinetic model of anion channelrhodopsin GtACR1 function.Biophysical journal · 2024Article
- Homeostatic regulation of rapid eye movement sleep by the preoptic area of the hypothalamus.eLife · 2024Article
- Bioluminescence as a functional tool for visualizing and controlling neuronal activityNeurophotonics · 2024Article
- Homeostatic regulation of REM sleep by the preoptic area of the hypothalamus.bioRxiv : the preprint server for biology · 2024Article
- Regulation of stress-induced sleep fragmentation by preoptic glutamatergic neurons.Current biology : CB · 2024Article
- Metadynamics simulations reveal mechanisms of Na+ and Ca2+ transport in two open states of the channelrhodopsin chimera, C1C2.PloS one · 2024Article
64 more citing papers are in PubMed but not listed here.
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19 authors at 6 institutions in 4 countries.
Funding
Abstract
The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near -65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼ 15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor-based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure-function relationships of the light-gated pore.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.