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Ion Channel Protein in Inner Ear Is Likely Long-sought Key to Hearing
To make sense of the famous first notes of a Beethoven symphony or the blare of car horns during rush hour, the ear must convert the noise into electrical signals understood by the brain.
A new picture for textbooks. A tuft of cilia sprouts from each of the 17,000 hair cells in the inner ear. The cilia bend back and forth at their bases, sliding past each other thousands of times a second (left). The key elements in converting sound into nerve impulses are located at the cilia tips. David Corey updates the classic textbook illustration (middle), incorporating recent discoveries from several labs and culminating in his new paper. The revised model (right) shows a relatively rigid filament of cadherin23 linking the channels, with TRPA1's springy tail of ankyrin repeats anchored by myosin-1c to the cilia's actin fibers. (Illustration by David Corey)
Now HMS researchers and their colleagues may have identified the essential protein deep in the inner ear that transforms sound waves into nerve impulses.
The scientists believe the ion channel protein, TRPA1, forms pores that quickly open and close in sync with sound waves. An open channel allows ions to flow into receptor cells of the inner ear, which translate the vibrations into electrical signals. The same protein channel also may selectively amplify sounds to help people distinguish between tones of different frequencies.
"Although we'd like further confirmation, experiments in three different species using many different methods all point to the same channel," said David Corey, a Howard Hughes investigator and HMS professor of neurobiology. Corey is the lead author of the study, published online Oct. 13 in Nature (doi: 10.1038).
| "This channel is the jewel everyone would like to find. Identifying it is getting at the real kernel of how the inner ear works." |
"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 proteins 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 findings have no immediate clinical application, but the discovery could help scientists investigate normal hearing and inherited forms of deafness, which typically involve other protein pieces of the same acoustic apparatus, said Corey, codirector of the HMS Center for Hereditary Deafness.
Mechanics of Hearing
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 external ear, which funnels sound down the ear canal. The vibrating ear drum nudges miniature bones in the middle ear, which transmit the beat to the inner ear.
Shuh-Yow Lin, Melissa Vollrath, David Corey, Kelvin Kwan (left to right), and their colleagues may have found the key ion channel that converts sound waves to nerve impulses in the inner ear. Corey appears on camera in a new piece on Lab Works, giving an explanation of the channel's apparent role in hearing. (Photo by Steve Gilbert)
Inside the spiraling cochlea, a coiled ribbon of hair cells hums in response to the surging pressure pulses. Different parts of the ribbon vibrate in response to different tones.
The tips of hair cells sway in double time to the sound, orchestrating a tiny system of molecular strings, springs, and levers, Corey said. With each cycle of sound, cilia protruding from the top of each hair cell bend back and forth. When they bend, a fine filament linking the tips tightens, yanking open the channel. Electric current flows through the open pore. The voltage change activates nerve synapses at the base of the hair cells. And a tangled network carries the signals to different places in the brain. A chat at the candy machine in the hallway travels to the language center, while the blare of the alarm clock jolts the arousal center with a morning wake-up call.
TRP Channel Stands Out
In their paper, Corey and his colleagues present three lines of evidence that the mysterious ion channel is actually TRPA1. TRP proteins are a family of ion channels involved in sensory perception. Different TRPs help insects see and hear and help mammals taste and sense heat and pheromones. A small clan known as TRPN (or NOMPC) helps fruit flies sense touch and fish hear. But the genomes of higher vertebrates, such as reptiles, birds, mice, and people, lack the instruction set to make TRPN channels.Corey and his colleagues first systematically evaluated all of the several dozen mouse TRP channels to locate the ones expressed in the tips of hair cell cilia. TRPA1 looked most promising in both frogs and mice.
As attractive as the protein appeared, it had to pass several other tests. When the researchers blocked TRPA1 expression in zebrafish, hair cells did not generate electrical signals in response to vibration. Nor did they show 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. They found no electrical activity in most hair cells they recorded with blocked TRPA1. Likewise, the hair cells did not take up the fluorescent dye.
The protein has a springy tail of amino acids. It could be the bungee cord-like element that pulls open the pore of the transduction channels, as Corey proposed 25 years ago, when he was a graduate student in the lab of James Hudspeth, now a Hughes investigator at Rockefeller University.
Corey speculates that the TRPA1 protein may help people distinguish between subtly different tones in a melody. In the cochlea, each region of hair cells is sharply tuned to a different frequency. If the hearing organ were unrolled, it would resonate like a player piano, with the highest notes vibrating at one end and the lowest at the other.
"A current hypothesis in auditory research is that the transduction channels not only respond to sound, but can selectively amplify different frequencies of sound to produce this tuning," Corey said. "If TRPA1 is also the cochlear amplifier protein, understanding its structure will help us understand how we can appreciate the subtle tonal variations in music."
--Carol Cruzan Morton