Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

'Holy Grail' of hearing: True identity of pivotal hearing structure is revealed

07.09.2007
Our ability to hear is made possible by way of a Rube Goldberg-style process in which sound vibrations entering the ear shake and jostle a successive chain of structures until, lo and behold, they are converted into electrical signals that can be interpreted by the brain. Exactly how the electrical signal is generated has been the subject of ongoing research interest.

In a study published in the September 6 issue of the journal Nature, researchers have shed new light on the hearing process by identifying two key proteins that join together at the precise location where energy of motion is turned into electrical impulses. The discovery, described by some scientists as one of the holy grails of the field, was made by researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health (NIH), and the Scripps Research Institute in La Jolla, CA.

“This team has helped solve one of the lingering mysteries of the field,” says James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. “The better we understand the pivotal point at which a person is able to discern sound, the closer we are to developing more precise therapies for treating people with hearing loss, a condition that affects roughly 32.5 million people in the United States alone.”

When a noise occurs, such as a car honking or a person laughing, sound vibrations entering the ear first bounce against the eardrum, causing it to vibrate. This, in turn, causes three bones in the middle ear to vibrate, amplifying the sound. Vibrations from the middle ear set fluid in the inner ear, or cochlea, into motion and a traveling wave to form along a membrane running down its length. Sensory cells (called hair cells) sitting atop the membrane “ride the wave” and in doing so, bump up against an overlying membrane. When this happens, bristly structures protruding from their tops (called stereocilia) deflect, or tilt to one side. The tilting of the stereocilia cause pore-sized channels to open up, ions to rush in, and an electrical signal to be generated that travels to the brain, a process called mechanoelectrical transduction.

Most scientists believe that the channel gates are opened and closed by microscopic bridges—called “tip links”—that connect shorter stereocilia to taller ones positioned behind them. If scientists could determine what the tip links are made of, they’d be one step closer to understanding what causes the channel gates to open. This is no easy feat, however, because stereocilia are extremely small, scarce, and difficult to handle. Several proteins had been reported to occur at the tip link in earlier studies, but results have been conflicting to this point.

Cadherin 23 and Protocadherin 15 Unite to Form Tip Link

Using three lines of evidence, NIDCD scientists Hirofumi Sakaguchi, M.D., Ph.D., Joshua Tokita, and Bechara Kachar, M.D., together with Piotr Kazmierczak and Ulrich Müller, Ph.D., of Scripps Research Institute, and other collaborators have demonstrated that two proteins associated with hearing loss—cadherin 23 (CDH23) and protocadherin 15 (PCDH15)—unite and adhere to one another to form the tip link. Mutations in CDH23 are known to cause one form of Usher syndrome as well as a nonsyndromic recessive form of deafness, and mutations in PCDH15 are responsible for another form of Usher syndrome. (A syndrome is a disease or disorder that has more than one feature or symptom, while the term “nonsyndromic” refers to a disease or disorder that is not associated with other inherited characteristics.) Usher syndrome is the most common cause of deaf-blindness in humans.

“Cadherin 23 and protocadherin 15 have been implicated in a variety of forms of late- and early-onset deafness, and a whole range of mutations can produce different outcomes,” says NIDCD’s Kachar, a co-senior investigator on the study. “Now that we know how these two proteins interact at the tip link, we can perhaps predict how different types of hearing loss can take place depending on where a mutation is located.”

Three Lines of Evidence

The researchers first created antibodies that would bind to and label short segments on the CDH23 and PCDH15 proteins in the inner ears of rats and guinea pigs. (Both proteins were identified at the tip link, respectively, in earlier studies.) Using green fluorescence and electron microscopy studies, they showed that CDH23 was located on the side of the taller stereocilium and PCDH15 was present on the tip of the shorter one, with their loose ends overlapping in between. The researchers were able to identify both proteins, while earlier studies had not, because they removed an obstacle to the antibody-binding process: calcium. Under normal conditions, CDH23 and PCDH15 are studded with calcium ions, which prevent antibodies from binding to the targeted sites. When calcium was removed through the addition of a chemical known as BAPTA, both labels became visible.

Next, the researchers built a structure resembling a tip link by expressing the CDH23 and PCDH15 proteins in the laboratory and watching how they interacted. When conditions were right, the two proteins wound themselves tightly together from one end to the other in a configuration that mirrored a naturally occurring tip link. The results were surprising, since the scientific consensus had been that these proteins would not interact at all. As with normal tip links, 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.

Lastly, the scientists found that one mutation of PCDH15 that causes one form of deafness inhibited the interaction of the two proteins, leading them to conclude that the mutation reduces the adhesive properties of the two proteins and prevents the formation of the tip link. In a second mutation of PCDH15, the tip link was not destroyed; the scientists suggested that the deafness is not likely caused by the breakup of the tip link but by interference with its mechanical properties.

Knowing precisely the composition and configuration of the tip link, scientists can now explore how these proteins interact with other components to form the rest of the transduction machinery. In addition, scientists can study how new treatments might be developed to address the breaking up of tip links through environmental factors, such as loud noise.

“Now that we understand what the tip link is made of and what conditions are required to assemble it,” says Kachar, “we can study what it might take to rejoin tip links as a possible method for restoring hearing in people with some forms of hearing loss that may have resulted from disruption of the tip link.”

Jennifer Wenger | EurekAlert!
Further information:
http://www.nih.gov
http://www.nidcd.nih.gov

More articles from Health and Medicine:

nachricht Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

nachricht Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Microscopic trampoline may help create networks of quantum computers

17.07.2018 | Information Technology

In borophene, boundaries are no barrier

17.07.2018 | Materials Sciences

The role of Sodium for the Enhancement of Solar Cells

17.07.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>