Protein in the Inner Ear "Missing Link" to Genetic Deafness

The NIDCD reported yesterday the discovery of a protein called protocadherin-15 (PC15)(which is associated with a form of genetic deafness called Usher Syndrome) as the likely player in the initial transduction of sound. As I have discussed here, the cochlea's sensory cells are called hair cells which project "hairs" into fluid spaces that vibrate when sound waves pass through. The "hairs" (called stereocilia) of each hair cell are connected by very important proteins called tip links. These links must be present for the transduction of sound to occur; when stereocilia are deflected, the tip links cause ion channels to open which changes the polarity of the hair cell. When there are no tip links, either due to a genetic flaw in the protein (Usher's syndrome), or the destruction of tip links by noise, the result is deafness.

Below is a SEM picture of a mouse hair cell. Notice how the stereocilia get progressively bigger, and they are in tight bundles. It is the tip link proteins that reinforce this structure and organization, and allow ion channels to open when the stereocilia are moved.
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(More under the fold....)

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The above picture is a "side view" of a hair cell, demonstrating how the tip links connect each stereocilia together in tandem.

The study was recently published in the Journal of Neuroscience, and the director of the NIDCD had this to say about it:

"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.. "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."

The team explore three alternative forms of PC15 found in the inner ear: CD1, CD2, and CD3. Any of these could have been the tip link protein. They used immunohistochemistry to determine that the distribution of PC15 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. The CD2 form is expressed along the lengths of stereocilia during hair cell development, but is not present in mature hair cells.

They also tested the effects of a toxin known to break tip links - called BAPTA - which had no effect on the CD1 and CD2 forms of P15 but destroyed the CD3 form. Tip links are known to reappear about 4 hours following loud noise exposure, and right on cue, four hours after the BAPTA was removed, the CD3 form returned.

All this evidence points to CD3 as the version of PC15 that is of the most interest, but it is likely that it works with the other forms of PC15 to complete sound transduction. The team hypothesized that the CD3 form of PC15, which is 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.

For more on hair cell mecahnotransduction, here is a fantastic summary.
Source: Will the Real Tip-Link Antigen Please Stand Up Zubair M. Ahmed et al. J. Neuro. June 2006.
The Tip-Link Antigen, a Protein Associated with the Transduction Complex of Sensory Hair Cells, Is Protocadherin-15. Zubair M. Ahmed et al. J. Neuro. June 2006. Abstract.

Thanks to Abel Pharmboy and others for emailing this story!

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Thanks for this great post.
I found the website: which has great info on the cochlea.
The "theory" page contains some stuff about mechanics of the cochlea. (I don't know if it's accurate, you tell us! :-))
What I find good is that they give papers' references for those who would like to get it full.

I have two questions for you:
1 - do we know the proteins involved in the ion channel? I mean the tip opens some stuff on the cell's membrane for potassium to get in, what is opened? and how does it work? (maybe it's not well known yet?)
2 - how is the tip reconstructed after damage? I mean, it is out of the cell, so how does the cell recreate it?

I also have a request:
could you show us cochlea (or equivalent structures) among various species? how do they compare, how do they differ, etc. (with nice pictures, as biologists know how to do :-)).

Hey Shelley,
Thanks so much for the great picture of the inner ear, the one you are showing on site is unique. I love the concepts of the hair in the inner ear. Its amazing to think that different sound waves trigger different nerves but the layered complexity of balance and equalibium just adds to my wonderment of the the whole system. Thanks and Blessing.
Robb Fogg
Teacher Xenia Ohio

By Robb Fogg (not verified) on 31 Oct 2007 #permalink