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Researchers at the University Medical Center Göttingen (UMG) and the Göttingen Cluster of Excellence "Multiscale Bioimaging" (MBExC) have shown how a minimal change in a single ion channel increases the sensitivity of sensory cells in the inner ear. Even soft sounds, such as a whisper, are perceived more clearly, but can cause prolonged overloading, which can ultimately lead to long-term hearing loss. These findings deepen our understanding of how sound information is encoded in the ear. The results have been published in the journal "Science Advances".
In the inner ear, sensory hair cells convert sound waves into electrical signals. When a sound wave hits the sensory hair cells in the inner ear, their hair bundles react in response to the intensity of the sound: a soft whisper causes a gentle deflection, while a louder tone causes more vigorous deflection. Through this hair bundle movement, hair cells activate calcium channels at their synapses, allowing for calcium influx. The incoming calcium triggers the release of a neurotransmitter, which transmits the electrical signal to auditory nerve cells. The electrical signal is then transmitted along the auditory pathway to the brain, where the sound is perceived.
Calcium channels of the type CaV1.3 play a crucial role in the transmission of signals from sensory hair cells to auditory nerve cells. They are highly sensitive to voltage changes in the cell, which are triggered by the incoming sound signal. Dysfunction of CaV1.3 channels can lead to impairments ranging from hearing problems to complete deafness. Possible causes of this loss of function may include mutations in the genetic blueprint of CaV1.3, which can lead to the formation of a dysfunctional channel.
A research team led by Prof. Dr. Tobias Moser, Director of the Institute for Auditory Neuroscience at the University Medical Center Göttingen (UMG) and Speaker of the Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), has now investigated the influence of a genetically modified CaV1.3 variant, known as CaVAG, on sound processing between sensory hair cells and auditory nerve cells in an animal model. The CaVAG variant is based on a tiny change in the blueprint of the calcium channel, but exhibits increased sensitivity to voltage changes in the sensory hair cell compared to the intact channel. This means that the CaVAG calcium channel has a lower activation threshold and opens in response to the same stimulus much sooner than an intact channel. The CaVAG variant of the CaV1.3 channel has also been described in humans and has been linked to an increased risk of autism spectrum disorders in children.
Together with their collaboration partners from the Shanghai Institute of Precision Medicine in China and the University of Innsbruck, Austria, the Göttingen researchers have now shown for the first time that the increased sensitivity of CaVAG calcium channels in the sensory hair cells has a direct impact on the sensitivity of the downstream auditory nerve cells and their response behavior to sound signals. As a result of the higher sensitivity of the CaVAG variant to voltage changes in sensory hair cells, the threshold of the downstream auditory nerve cells, which transmit sound information to the brain, is also lowered. This also affects the spontaneous activity of the auditory nerve cells, which are now more active even in complete silence, without any sound stimulus.
“While the increased sensitivity of the altered CaV1.3 channel may help to better perceive soft sounds more clearly in the short term, our animal model showed that some synapses between sensory hair cells and auditory nerve cells ultimately lose their structure over time – without any exposure to loud music or other noise. The ‘normal’ background noise in the animal house alone is apparently sufficient for this. It looks as if the overactive calcium influx caused by the mutation overloads the system," says Prof. Moser, the last author of the study. "We could be seeing a new form of gradual hearing damage on a molecular level - a kind of hidden hearing loss that cannot be detected with standard hearing tests."
The results have been published in the journal "Science Advances".
Original publication:
Karagulyan N, Thirumalai A, Michanski S, Qi Y, Fang Q, Wang H, Ortner NJ, Striessnig J, Strenzke N, Wichmann C, Hua Y, Moser T. Gating of hair cell Ca2+ channels governs the activity of cochlear neurons. Science Advances (2025). DOI: https://doi.org/10.1126/sciadv.adu7898
What does this mean for people?
"Given the severity of the condition, it is almost impossible to investigate the hearing abilities of individuals who carry the CaVAG variant of the calcium channel. The new findings suggest that such individuals may be particularly sensitive to sound and at the same time highly susceptible to noise-induced damage. The study therefore recommends monitoring affected individuals audiologically over the long term and suggests considering preventive hearing protection in everyday noise exposure.
The Göttingen Cluster of Excellence MBExC
The Göttingen Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC) has been funded since January 2019 as part of the Excellence Strategy of the German federal and state governments. With a unique research approach, MBExC investigates the disease-relevant functional units of electrically active heart and nerve cells, from the molecular to the organ level, using innovative imaging techniques such as optical nanoscopy, X-ray imaging and electron tomography. To this end, MBExC brings together numerous university and non-university Göttingen Campus partners. The overarching goal: to understand the connection between heart and brain diseases, to carry out basic and clinical research and to develop new methods.
Prof. Dr. Tobias Moser
Institute of Auditory Neuroscience
Cluster of Excellence “Multiscale Bioimaging” (MBExC)
Collaborative Research Center 1690
Phone +49 551 / 39-63071
tobias.moser@med.uni-goettingen.de
www.auditory-neuroscience.uni-goettingen.de
Karagulyan N, Thirumalai A, Michanski S, Qi Y, Fang Q, Wang H, Ortner NJ, Striessnig J, Strenzke N, Wichmann C, Hua Y, Moser T. Gating of hair cell Ca2+ channels governs the activity of cochlear neurons. Science Advances (2025). DOI: https://doi.org/10.1126/sciadv.adu7898
http://www.auditory-neuroscience.uni-goettingen.de - Institute of Auditory Neuroscience
https://mbexc.de/en/ - Cluster of Excellence „Multiscale Bioimaging” (MBExC)
Senior author Prof. Dr. Tobias Moser, director of the Institute of Auditory Neuroscience at the Univ ...
Copyright: umg/swen pförtner
First author Dr. Nare Karagulyan, Postdoctoral researcher at the Institute of Auditory Neuroscience ...
Copyright: umg/swen pförtner
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