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Proteins Pair to Form Crucial Hearing Structure

Neatly arranged rows of stereocilia sit atop a hair cell of the inner ear. Microscopic tethers called "tip links" connect the tops of shorter stereocilia to the taller ones behind them. Bechara Kachar, NIDCD.

Scientists have identified 2 proteins that appear to pair up at the precise location in the ear where sound vibrations are turned into electrical signals. The finding may eventually help researchers develop more precise treatments for hearing loss, a condition that affects more than 32 million people in the United States alone.

When a car horn honks or a person laughs, sound vibrations travel through the air until they reach your ear and bounce against the eardrum, triggering a chain of events that you ultimately perceive as sound. Researchers have long tried to learn exactly how the motion energy of sound is transformed into electrical impulses that the brain can understand. They knew that sensory cells in the inner ear called hair cells are crucial to the process.

Sitting atop the hair cells are tiny bristly structures known as stereocilia. As hair cells move in response to sound, their stereocilia bump up against a membrane, causing them to tilt. Microscopic tethers called "tip links" connect rows of shorter stereocilia at their tips to taller stereocilia behind them. Most scientists believe that as the stereocilia move and tilt, the tip links open up tiny cellular pores, allowing electrically charged ions to rush into the hair cells. This inrush begins an electrical signal that travels to the brain.

Scientists at NIH's ×îÐÂÂ鶹ÊÓƵ Institute on Deafness and Other Communication Disorders (NIDCD) and the Scripps Research Institute set out to identify the molecular components of the tip links. Although previous studies had reported finding several different protein components, their results were often conflicting.

In the September 6, 2007, edition of Nature, the researchers report that 2 proteins already associated with hearing loss — cadherin 23 and protocadherin 15 — unite and adhere to one another to form the tip link. The scientists used electron microscopy to show that cadherin 23 links to the side of the longer stereocilium, while protocadherin 15 connects to the tip of the shorter one.

The researchers also found that, under the right conditions, cadherin 23 and protocadherin 15 could form a structure in the laboratory that resembles a tip link. The two proteins can wind tightly together from one end to the other in a configuration that mirrors a naturally-occurring tip link. The structure thrived in calcium concentrations that paralleled those found in fluid of the inner ear, while a drastic reduction in calcium disrupted the structure.

The researchers found that one deafness-causing change in protocadherin 15 inhibited its interaction with cadherin 23. They concluded that the mutation reduces the adhesive properties of the 2 proteins and blocks formation of the tip link.

"Now that we understand what the tip link is made of and what conditions are required to assemble it, we can study what it might take to rejoin tip links," says NIDCD’s Dr. Bechara Kachar, a co-senior investigator on the study. Therapies that reunite the proteins may one day help to restore hearing in people with some forms of hearing loss.