U. Va. researchers unravel a central mystery of how hearing happens

October 13, 2004

CHARLOTTESVILLE, Va., Oct. 13, 2004 - Scientists at the University of Virginia Health System have helped solve the mystery of how the human ear converts sound vibrations and balance stimuli into electrical impulses the brain can interpret. Their research is detailed in the October 13 advance online edition of the journal Nature, found at www.nature.com/nature .

Neuroscience researchers Jeffrey Holt and Gwenaëlle Géléoc, working in collaboration with scientists elsewhere, discovered a long-sought protein called TRPA1 that is located at the tips of the tiny sensory cells in the inner ear. They found that TRPA1 converts sound into nerve impulses, which are transmitted to the brain. Identification of the protein and the gene that encodes TRPA1, could allow for future treatments for deafness. "This is one of the most significant findings in sensory biology, detailing an ingeniously simple, but remarkably sensitive system," said Holt, an assistant professor of neuroscience and otolaryngology at the U.Va. Health System.

"For hearing researchers, this discovery is the holy grail in understanding the function of both hearing and balance," said Jeffrey Corwin, professor of neuroscience at U.Va. The protein TRPA1 works by forming a channel resembling a donut in the cell membrane of inner ear hair cells. "In the absence of sound, the hole is closed, "Holt explained. "But when sound strikes the protein, the hole pops open like a trap door, allowing potassium and calcium ions to flood into the cells. Because these elements carry a positive charge, an electrical signal is generated which is relayed to the brain for interpretation."

Now that this genetic link to hearing has been established, Holt said, geneticists can examine the gene that encodes TRPA1 in deaf patients, some of whom he expects may have a mutated form of the TRPA1 gene.

"This could allow for the development of new gene therapies for deafness and balance disorders in the next five to ten years," Holt said. "Essentially, if we could take a correct copy of the gene and reintroduce it into the cells of the inner ear, we might be able to restore hearing and balance function in people with hereditary inner ear disorders."

A large body of circumstantial evidence has accumulated over the past 25 years that suggests a mechanically sensitive, donut-shaped protein must be at the heart of the body's hearing apparatus, but scientists had no idea of what it was, despite intense effort. Holt and Géléoc previously identified an 18-hour window for the functional development of inner ear hair cells in mouse embryos. This breakthrough helped them identify that the TRPA1 gene was turned on during the same 18-hour period, sending the U.Va. scientists down the path to discovery.

"Now that we've identified TRPA1 as the hair cell transduction channel," Géléoc said, "this opens a window of opportunity with significant implications for the field of hearing and deafness research and beyond, including the fields of engineering and nanotechnology."

The husband and wife team of Holt and Géléoc, an assistant professor of research in neuroscience and otolaryngology at U.Va., worked in collaboration with scientists at Northwestern University, Duke University, Harvard Medical School and the National Institutes of Health.

"This represents science at its best," Holt said. "We approached this question from a number of angles, with a number of different techniques and in a number of different research labs. The fact that we collaborated and came up with the same answer independently allows us to make a much more convincing scientific argument than any one scientist or lab could have done on their own."
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University of Virginia Health System

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