Scientists from The Scripps Research Institute have elucidated the action of a protein, harmonin, which is involved in the mechanics of hearing.
This finding sheds new light on the workings of mechanotransduction, the process by which cells convert mechanical stimuli into electrical activity. Defects in mechanotransduction genes can cause devastating diseases, such as Usher's syndrome, which is characterized by deafness, gradual vision loss, and kidney disease, which can lead to kidney failure.
The research, led by Scripps Research Professor Ulrich Mueller, was published in the May 14, 2009 issue of the journal Neuron.
"We're constantly confronted with mechanical signals of many different kinds and we have sensors all over our bodies that respond to those signals," Mueller says. "For example, mechanosensors in the muscles control posture, while those in skin allow us to feel touch. Though many of our other senses, such as taste and smell, are well understood, mechanosensory perception is a world about which we know next to nothing."
By gaining a better appreciation of the molecular mechanics of hearing, scientists can learn a great deal about the workings of similar types of body processes and the defects in these processes that can cause disease.
Hearing: An Exquisite Molecular Dance
Sound starts as waves of mechanical vibrations that travel through the air to the ear by compressing air molecules. The waves first hit the outer ear, then travel down the ear canal into the middle ear before striking the eardrum. The vibrating eardrum moves a set of delicate bones that communicate with a fluid-filled spiral structure in the inner ear, the cochlea. Inside the cochlea are specialized "hair cells" lined with symmetric arrays of stereocilia - mechanosensing organelles that respond to fluid motion or fluid pressure changes. The movement of the fluid inside the cochlea causes the stereocilia, in turn, to move.
When sterocilia are deflected, molecular complexes called "tip links," which connect the tips of stereocilia, transmit physical force to the gated ion channels that are attached to them. The opening of these ion channels, which are monitored by sensory neurons, communicate the electrical signals to neurons in the brain, enabling hearing. In Usher syndrome and some other sensory neuronal diseases that cause deafness, the symmetry of the stereocilia - and the process of mechanotransduction - is disrupted, resulting in deafness.
"It has been known for some time that defects in the hair cells make people deaf, but no one knew why - it was thought that perhaps synapses in the hair cells somehow degenerate or the cells don't develop normally," Mueller says. "The idea that the hair cells' basic function as mechanotransducers were impaired as a result of molecular defects has never been shown before."
Building on Earlier Research
In part because stereocilia are extremely small, scarce, and difficult to handle, the molecules that make up the tip link remained elusive until 2007, when Mueller and his colleagues identified cadherin 23 and protocadherin 15 as the two proteins responsible for opening the ion channels. They also showed that cadherin 23 formed a complex with another protein, myosin 1c, which helped close the channel.