Key Hearing Proteins Identified

Researchers have found what appear to be 2 key components of the long-sought-after mechanotransduction channel in the inner ear—the place where sound waves are transformed into the electrical signals that the brain recognizes as sound.

Photo of a young woman cupping her hand to her ear.

Sensory cells in the inner ear called hair cells are crucial for transforming sound into electrical signals. Hair cells also underlie our sense of balance. Sitting atop hair cells are tiny bristly structures called stereocilia. Microscopic tethers connect the tips of shorter stereocilia to the sides of adjacent taller stereocilia. Most scientists believe that as the stereocilia move, the tethers open ion channels—tiny openings in the cell that let electrically charged molecules (ions) pass in and out. The ions rushing inside begin an electrical signal that travels to the brain.
While researchers have gained many insights into mechanotransduction, the ion channels involved have remained elusive. A team of researchers led by Dr. Andrew J. Griffith of NIH's National Institute on Deafness and Other Communication Disorders (NIDCD) and Dr. Jeffrey R. Holt of Harvard Medical School decided to focus on 2 proteins. Griffith and other collaborators had previously found that mutations in the TMC1 gene cause hereditary deafness in both humans and mice. The TMC1 protein sequence suggests that it could span the cell's outer membrane and act as a channel. Another protein, TMC2, has a similar structure. The scientists deleted both genes in mice. Their findings appeared on December 1, 2011, in the Journal of Clinical Investigation.
Mice with no functional copies of TMC1 or TMC2 had the classic behaviors of dizzy mice—head bobbing, neck arching, unstable gait and circling movements. They were also deaf. The TMC1 deficient mice were deaf as well, but had no balance issues. Mice without TMC2 had no problems with hearing or balance.
The scientists examined when the TMC1 and TMC2 genes are expressed (turned on) in the inner ears of mice. The 2 genes were expressed from birth in hair cells in both the cochlea, which is responsible for hearing, and the vestibular organs, which are responsible for balance. When mice were a week old, TMC2 appeared to be turned off in the cochlea but not in the vestibular organs. TMC1 continued to be expressed in mature cochlear hair cells. Taken toghter, these findings suggest that TMC1 is essential for hearing, but TMC2 is not. For balance, however, TMC2 can substitute for TMC1.
In laboratory tests, hair cells lacking functional TMC1 or TMC2 had no detectable mechanotransduction currents, even though the rest of the cells' structure and function appeared normal. By using a gene therapy technique that adds proteins back into cells, the researchers were able to restore transduction to both vestibular and cochlear hair cells. This finding suggests that it might be possible to reverse these genetic deficits.
The researchers found that TMC1 and TMC2 cluster at the tips of the stereocilia, where one might expect to see proteins that play a prominent role in mechanotransduction. In future work, the scientists intend to explore how TMC1 and TMC2 interact with each other as well as with other known proteins at the stereocilia tip.