Biology subjects

Mager, T.

Publications and source records attributed to Mager, T..

4 recordsLinked to original sources

bioRxiv2026

Multichannel optical cochlear implants enable spectrally distinct auditory activity

When hearing fails, cochlear implants (CIs) restore auditory perception. Yet, coding of spectral information remains a bottleneck because each electrode broadly activates the auditory nerve. As light can be more conveniently confined, optical (o)CIs present an alternative. Here, we combined expression of the potent channelrhodopsin ChReef in spiral ganglion neurons (SGNs) with oCIs comprising 5-10 green LEDs in gerbils. This combination enabled systematic comparison of encoding intensity and spectral information by individual oCI channels to acoustic and electrical stimulation within a translationally feasible energy range. Recordings from the inferior colliculus (ICC) showed that ChReef aligned SGN light sensitivity with LED radiant fluxes: ICC activity had thresholds <200 nJ and reached a maximum equivalent to that achieved with 51 dB SPL pure tones. Multichannel oCIs enabled tonotopically ordered, spectrally distinct stimulation that more closely resembled acoustic stimulation than did electrical stimulation. Some LEDs elicited multiple spectral peaks at higher intensities. Linear discriminant analysis of ICC activity indicated improved channel discriminability for optical over electrical stimulation. In summary, ,micro-joule oCI-stimulation achieves improved spectral resolution over state-of-the-art electrical stimulation.

neuroscience↗

bioRxiv2024

CryoRhodopsins: a comprehensive characterization of a new clade of microbial rhodopsins from cold environments

Microbial rhodopsins are omnipresent on Earth, however the vast majority of them remain uncharacterized. Here we describe a new rhodopsin group from cold-adapted organisms and cold environments, such as glaciers, denoted as CryoRhodopsins (CryoRs). Our data suggest that CryoRs have dual functionality switching between inward transmembrane proton translocation and photosensory activity, both of which can be modulated with UV light. CryoR1 exhibits two subpopulations in the ground state, which upon light activation lead to transient photocurrents of opposing polarities. A distinguishing feature of the group is the presence of a buried arginine residue close to the cytoplasmic face of its members. Combining single-particle cryo-electron microscopy and X-ray crystallography with the rhodopsin activation by light, we demonstrate that the arginine stabilizes a UV-absorbing intermediate of an extremely slow CryoRhodopsin photocycle. Together with extensive spectroscopic characterization, our investigations on CryoR1 and CryoR2 proteins reveal mechanisms of photoswitching in the newly identified group and demonstrate principles of the adaptation of these rhodopsins to low temperatures.

biophysics↗

bioRxiv2023

Efficient and sustained optogenetic control of nervous and cardiac systems

Optogenetic control is used to manipulate the activity of specific cell types in vivo for a variety of biological and clinical applications. Here we report ChReef, an improved variant of the channelrhodopsin ChRmine. ChReef offers minimal photocurrent desensitization, a unitary conductance of 80 fS and closing kinetics of 30 ms, which together enable reliable optogenetic control of cells at low light levels with good temporal fidelity and sustained stimulation. We demonstrate efficient and reliable red-light pacing and depolarization-block of ChReef-expressing cardiomyocyte clusters. We used AAV-based gene transfer to express ChReef in retinal ganglion cells, where it restores visual function in blind mice with light sources as weak as an iPad screen. Toward optogenetic hearing restoration, ChReef enables stimulation of the auditory pathway in rodents and non-human primates with nano-Joule threshold, enabling efficient and frequency-specific stimulation by LED-based optical cochlear implants.

biophysics↗

bioRxiv2018

Electron cryo-microscopy structure of the canonical TRPC4 ion channel

Canonical transient receptor channels (TRPC) are non-selective cation channels. They are involved in receptor-operated Ca2+ signaling and have been proposed to act as store-operated channels (SOC). Their malfunction is related to cardiomyopathies and their modulation by small molecules has been shown to be effective against renal cancer cells. The molecular mechanism underlying the complex activation and regulation is poorly understood. Here, we report the electron cryo-microscopy structure of zebrafish TRPC4 in its unliganded (apo), closed state at an overall resolution of 3.6 [A]. The structure reveals the molecular architecture of the cation conducting pore, including the selectivity filter and lower gate. The cytoplasmic domain contains two key hubs that have been shown to interact with modulating proteins. Structural comparisons with other TRP channels give novel insights into the general architecture and domain organization of this superfamily of channels and help to understand their function and pharmacology.

biochemistry↗