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BOSTON-October 13, 2004-Researchers at Harvard Medical School and their
colleagues report in the October 13 Nature advanced on-line edition that
they have identified a protein deep in the inner ear that they believe
translates sound into the nerve impulses used by the brain.
"People have been looking for this protein for a decade," says David
Corey, HMS professor of neurobiology and an investigator of the Howard
Hughes Medical Institute. Other protein candidates have been nominated,
but this is "the strongest evidence yet that this protein is the hair-cell
transduction channel," says Corey, lead author of the paper.
The discovery could help scientists investigate normal hearing and
inherited forms of deafness, which typically involve other protein pieces
of the same acoustic apparatus, says Corey, also co-director of the HMS
Center for Hereditary Deafness.
"This is the most important molecule in the ear," said Peter Gillespie, a
neurobiologist at Oregon Health & Science University who recently has
helped identify important parts connecting to either side of the channel.
"This channel is the jewel everyone would like to find. Identifying it is
getting at the real kernel of how the inner ear works."
The protein, TRPA1 (pronounced TRIP-AY-ONE), is located at the tips of
specialized cilia on hair cells of the inner ear. Scientists believe the
protein forms pores that open and close in sync with sound waves, allowing
ions to flow into the cells and to transform the vibrations into electric
signals. The same protein channel also may help people distinguish between
tones of different frequencies.
Sound travels through the auditory system like a message relayed through
the jungle from drum to drum. Snippets of conversation or the roar of a
leaf blower are collected by the fleshy outer part of the ear and funneled
inside where a delicate percussion section vibrates, taps and shivers.
The key elements in converting sound into nerve impulses are the bundles
of cilia that protrude from the tops of hair cells and give them their
name. Inside the cochlea, the stiff cilia bend at their bases when the
pulsing sound waves push against them thousands of times a second. Small
protein strings called tip links connect the tip of each cilium with its
taller neighbor. (Six months ago, other researchers discovered the
molecular identity of the tip links.) With each vibration, the bending
cilia pull on the links connecting them, yanking open the channels to
allow ions to flood into the cilia. The resulting voltage change activates
the conversion of sound to a nerve signal. Then, the cilia bend back and
ion channels snap shut.
"Hair cells convert a mechanical stimulus into an electrical signal with
molecular, strings, springs and levers," Corey says. "It's cell biology,
but it's wonderfully mechanical as well."
In their paper, Corey and his colleagues present evidence that the
mysterious ion channel is actually TRPA1. The TRP proteins are a trendy
new family of ion channels involved in sensory perception. Different TRP
proteins help insects see and hear, mammals taste and sense heat and
pheromones. A small clan known as TRPN help fruit flies sense touch and
fish hear.
At the beginning of their study, Corey and his colleagues systematically
evaluated all of the several dozen mouse TRP channels with RNA probes to
locate the ones expressed by hair cells of the mouse cochlea. TRPA1 looked
most promising. Using antibodies to TRPA1, the team found that the
channels were located at the tips of hair cell cilia.
As attractive as the protein appeared, it had to pass several other
rigorous tests made possible by scientific advances in the last several
years. In zebrafish, the researchers blocked expression of the TRPA1
protein and found their hair cells did not generate electrical signals in
response to vibration. In a related test, these hair cells showed none of
the telltale glow when exposed to a fluorescent dye that usually pours in
through working transduction ion channels.
In the third set of experiments, collaborators at the University of
Virginia School of Medicine genetically blocked the TRPA1 channel in hair
cells of embryonic mice, using siRNAs carried in with adenoviruses, and
measured the response. They recorded barely any electrical activity in the
hair cells with blocked TRPA1. Likewise, the hair cells did not take up
the fluorescent dye. Although the discovery needs confirmation by other
methods, TRPA1 is the best candidate for the hair-cell transduction
channel.
What are the implications for hearing and deafness? "Other protein
components of the transduction apparatus cause inherited deafness and
blindness when mutated," Corey says. "Although there is no evidence for it
at the moment, the same may be true for TRPA1. Having the transduction
channel will accelerate a search for the remaining protein pieces, and
these in turn may be causes of inherited deafness."
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