The findings will not only provide insight into how hearing takes place at the molecular level, but also may help us figure out why some people temporarily lose their hearing after being exposed to loud noise, only to regain it a day or two later.
Stereocilia are arranged in three tiers atop a hair cell; Inset: Tip links connecting shorter stereocilia to their taller neighbors. Credit: Reproduced with permission from Nature Reviews Genetics 5, 489–98 copyright 2004 Macmillan Magazines Ltd.
"These findings offer a more precise picture of the complicated processes involved with our sense of hearing," says Elias A. Zerhouni, M.D., director of the NIH. "With roughly 15 percent of American adults reporting some degree of hearing loss, it is increasingly vital that we continue making inroads into our understanding of these processes, helping us seek new and better treatments, and opening the doors to better hearing health for Americans."
Tapping Your Inner "Tip Link"
Researchers have long known that hair cells, small sensory cells in the inner ear, convert sound energy into electrical signals that travel to the brain, a process called mechanotransduction. However, the closer one zooms in on the structures involved, the murkier our understanding becomes. When fluid in the inner ear is set into motion by vibrations emanating from the bones of the middle ear, the rippling effect causes bristly structures atop the hair cells to bump up against an overlying membrane and to deflect. Like seats in a three-row stadium, the bristles, called stereocilia, are arranged in tiers, with each lower seat connected to a higher seat by minute, threadlike bridges, or links. As the stereocilia are deflected, pore-like channels on the surface of the stereocilia open up, allowing potassium to rush in, and generating an electrical signal. Because the "tip link" – the link that connects the tip of the shorter stereocilium to the side of the adjacent, taller stereocilium – must be present for the channel to function, scientists believe that this structure may be responsible for opening and closing the channel gate. Researchers suggest that if they can learn the makeup of the tip link, they'll be that much closer to understanding how the gate mechanism operates.
"This research identifies protocadherin-15 to be one of the proteins associated with the tip link, thus finally answering a question that has been baffling researchers for years," says James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. "Thanks to the collaborative effort among these researchers, we are now at the closest point we have ever been to understanding the mechanism by which the ear converts mechanical energy – or energy of motion – into a form of energy that the brain can recognize as sound."
NIDCD's Zubair M. Ahmed, Ph.D., and Thomas B. Friedman, Ph.D., together with the University of Sussex's Richard Goodyear, Ph.D., and Guy P. Richardson, Ph.D., and others used several lines of evidence to identify a protein that Drs. Goodyear and Richardson had earlier found to comprise tip links in the inner ears of young chicks. The protein is referred to as the "tip-link antigen" (TLA) because it induces the production of special antibodies, which bind to the protein at the stereocilia tips.
Using mass spectrometry, a laboratory technique that breaks down a substance into its individual components, the researchers analyzed the makeup of the TLA and found two peptide sequences that match up to key segments of the protein protocadherin-15 in humans, mice, and chickens, suggesting that the two proteins are evolutionarily comparable. Additional experiments using western blot analysis, a technique that identifies individual proteins in a substance by separating them from one another by mass and testing how they react to certain antibodies, demonstrated that the antibody that recognizes protocadherin-15 in mice also binds to the TLA.
The team also analyzed the amino acid sequences of protocadherin-15 and discovered four distinct forms -- three of which are present in various developmental stages of the mouse inner ear. The researchers refer to the three alternative forms found in the inner ear as CD1, CD2, and CD3 because the sequential variations occur in the protein's "cytoplasmic domain" – a stretch of amino acids anchored inside the stereocilium. (The fourth form, referred to as SI, is likely to be secreted.) With the help of two imaging techniques that use antibodies to label a targeted protein, the team found that the distribution of protocadherin-15 along the stereocilium varies by form, with the CD3 form stationed only at the tips of the stereocilia in mature hair cells, while the CD1 form is found along the lengths of the stereocilia in mature cells, but not at the tips. In contrast, the CD2 form is expressed along the lengths of stereocilia during hair cell development, but is not present in mature hair cells.
Finally, the team found that a chemical known to break tip links – called BAPTA – had no effect on the CD1 and CD2 forms of protocadherin-15 but destroyed the CD3 form. Likewise, just as tip links are known to reappear roughly four hours after the chemical is removed, the CD3 form returned within four to 24 hours upon removal of the chemical.
Based on these findings, the researchers conclude that, not only is protocadherin-15 now identified as the tip-link antigen, but it is distributed in a specific way in relation to the tip-link complex. They propose that the CD3 form of protocadherin-15, located at the tip of the shorter stereocilium, may link directly or indirectly to the CD1 form on the adjacent, taller stereocilium. This scenario could help explain how tip links that are broken in real-life situations, such as from excessive exposure to loud noise, could cause temporary hearing loss until the link re-establishes itself and hearing is restored.
In future studies, the scientists plan to delve more deeply into the role that protocadherin-15 plays in the tip-link complex and whether it interacts with other components in the formation of the tip link. They also hope to determine how tip links can be stimulated to re-form, once broken.
Jennifer Wenger | EurekAlert!
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