In a finding with implications for the future of optogenetics, scientists in Germany have discovered that a widely used light-sensitive ion channel exhibits two distinct light-activated states. The newly identified state allows the channel to reopen faster, improving its ionic conductivity and responsiveness – key traits for fine-tuned control of neuronal activity.
The study focuses on GtACR1, a channelrhodopsin from the marine alga Guillardia theta that has become a workhorse in optogenetic applications. Channelrhodopsins are proteins that respond to light by opening an ion channel, modulating the electrical activity of cells – especially neurons. Because of its high efficiency and fast kinetics, GtACR1 is considered one of the most promising candidates for therapeutic optogenetics.
Using Fourier transform infrared spectroscopy, the research team – based at Ruhr University Bochum and the University of Regensburg – tracked subtle structural changes in the protein as it responded to light. They found that, in addition to the canonical ground state cycle, GtACR1 passes through a light-sensitive intermediate called the O-intermediate. Unlike in other channelrhodopsins, this intermediate retains light responsiveness, enabling a second activation route.
“The second light-activated state we discovered ensures that the channel can be reopened particularly quickly, which significantly increases its ionic conductivity,” said Kristin Labudda, one of the study's lead authors.
The team’s spectral analysis showed that the retinal chromophore – the molecule within GtACR1 that captures light – adopts a conformation in the O-intermediate that preserves photosensitivity. This gives the channel a kind of "reset switch," allowing for reactivation without needing to return all the way to the dark-adapted ground state.
That capability is particularly appealing for optogenetic applications, where high-frequency or high-precision stimulation is often required. Faster reopening allows for more finely controlled modulation of neural circuits, with potential relevance for treating neurological disorders like Parkinson’s disease.
“With our work, we have discovered a channelrhodopsin with multiple light-activated states for the first time,” said Carsten Kötting, Associate Professor, who co-led the study. “It should be possible to create additional light-activated states in other channelrhodopsins through mutations, thus increasing their effectiveness.”
The findings suggest that the optogenetic toolkit could be further expanded by engineering similar intermediate states in other light-responsive proteins – pushing the field closer to highly personalized neural therapies.
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