November 2, 2004
Scientists Find ‘Holy Grail’ of Hearing Research
CHICAGO—Northwestern University neuroscientists and colleagues have identified a protein long considered to be the missing link in hearing research, a finding that may eventually lead to gene therapies for deafness.
In the online version of the journal Nature, Jaime Garcia-AÃ±overos, PhD, Anne Duggan, PhD, and co-researchers described the protein, TRPA1, which is the mechanosensory channel of hair cells, the sensory cells of the inner ear used for hearing as well as detecting gravity and maintaining balance.
TRPA1 transduces—or converts—sound waves into nerve impulses, the signals that are sent to the brain.
“This channel has been called the ‘holy grail’ of auditory research for the past two decades,” said Dr. Garcia-AÃ±overos, assistant professor of anesthesiology, neurology, and physiology at Northwestern University’s Feinberg School of Medicine and a scientist at the Northwestern University Institute for Neuroscience (NUIN).
“What is equally remarkable is that this protein is also essential for sensing pain. It might well be the most relevant molecule—the most important gene, really—for the senses,” said Dr. Garcia-AÃ±overos, who began studies on the role of TRPA1 in sensory research in the late 1990s with colleagues Dr. Duggan and David P. Corey, PhD, at Harvard Medical School. (Dr. Duggan is now research assistant professor of anesthesiology at the Feinberg School and NUIN scientist.)
In hearing, sound waves vibrate the eardrum, which makes tiny bones called ossicles move and tap against a snail-shaped, fluid-filled structure called the cochlea, where hair cells produce TRPA protein.
Vibrations passed to the cochlea change the pressure of the fluid inside, moving the hair-like structures called stereocilia that characterize the hair cells. TRPA1, present in those “hairs,” is the switch that is turned on when this displacement occurs, in response to sound.
Structures attached to the cilia control the opening and closing of the donut-shaped TRPA1 channel, which resembles a pore, in the membrane.
When the channel opens in response to sound, it allows positively charged potassium and calcium ions to flow into the cells, subsequently causing electrical signals, or pulses, to telegraph the pitch, volume, and duration of a sound to the brain.
In a series of experiments in mice hair cells and zebrafish embryos, the researchers determined that TRPA1 is found in a channel located on the tips of the ear’s tiny hair cells—a channel that is common to humans, mice, and fish.
The scientists found that hair cells that did not have TRPA1 on their tips did not convert vibrations into electrical impulses; that is, mice and zebrafish whose hair cells had no TRPA1 would be deaf.
Moreover, in mice embryos, the investigators found that TRPA1’s appearance during mouse development occurred at the same time in development when hair cells are able to sense vibrations.
Findings from the group’s study could lead to new therapies not only for hearing and balance disorders, but also for developing innovative pain treatments.
Collaborating with Dr. Garcia-AÃ±overos on this research were scientists from NUIN, Harvard Medical School, Boston’s Dana-Farber Cancer Institute, the University of Virginia School of Medicine, Massachusetts Institute of Technology, Harvard-Partners Genome Center, Duke University Medical Center, and the National Institutes of Health.