Scientists say they have ended a 40-year-quest for the elusive identity of the sensor protein responsible for hearing and balance.

The results of their research, reported in Neuron, reveal that TMC1, a protein discovered in 2002, forms a sound- and motion-activated pore that allows the conversion of sound and head movement into nerve signals that travel to the brain--a signaling cascade that enables hearing and balance.

Scientists have long known that when the delicate cells in our inner ear detect sound and movement, they convert them into signals. Where and how this conversion occurs has been the subject of intense scientific debate. No more, the authors say.

"The search for this sensor protein has led to numerous dead ends, but we think this discovery ends the quest," said co-senior author on the study. "We believe our findings settle that issue for good and yield definitive proof that TMC1 is the critical molecular sensor that converts sound and motion into electrical signals the brain can understand," said the other co-senior author. "It is, indeed, the gatekeeper of hearing."

The researchers say their findings lay the groundwork for precision-targeted therapies to treat hearing loss that occurs when the TMC1 molecular gate is malformed or missing.

Hearing loss is the most common neurologic disorder affecting more than 460 million people worldwide.

The senses--vision, touch, taste, pain, smell and hearing--help animals navigate the world and survive in it. The conversion of sensory input into signals that travel to the brain for analysis and interpretation is central to this process.

The "molecular converters" for most senses have been identified. The one for hearing, however, remained elusive, partly due to the hard-to-access anatomical location of the inner ear--within the densest bone of the human body--and partly because of the comparatively few auditory cells available for retrieval, dissection and imaging. The human retina has a hundred million sensory cells, compared with a precious few 16,000 in the human inner ear.

In an initial set of experiments, the research team found that TMC1 proteins assemble in pairs to form sound-activated pores, or ion channels. Given that most ion-channel proteins form clusters of three to seven units, TMC1's minimalistic pairing was a surprise. It also offered a helpful clue into its structure.

Next, to map out the molecular architecture of the TMC1 protein, the scientists turned to computer predictive modeling. Such models work by predicting the most probable arrangement of a protein's building blocks based on the configuration of a close relative with a known structure. The algorithm revealed that TMC1's closest relative with known structure was a protein known as TMEM16.

Each protein's function is determined by its structure--the specific sequence and arrangement of amino acids, the building blocks of proteins. TMEM16's amino acid arrangement yielded a possible amino acid model for TMC1.

But to verify the accuracy of the model and to pinpoint the precise location of the sound-activated pores, the researchers had to take their model out of the digital realm and into the real world of living hair cells of mice.

Substituting 17 amino acids--one at a time--the researchers gauged whether and how each single substitution altered the cells' ability to respond to sound and allow the flow of ions.

Of the 17 amino acid substitutions, 11 altered the influx of ions, and five did so dramatically, reducing ion flow by up to 80 percent, compared with nonmodified cells. One particular substitution blocked calcium influx completely, a finding that confirmed the precise location of the pore that normally allows calcium and potassium influx to initiate signal transmission.

TMC1 is found in mammals, birds, fish, amphibians and reptiles--a sign of evolutionary conservation at work.

"The fact that evolution has conserved this protein across all vertebrate species underscores how critical it is for survival," author said.

The ability to hear a sound and distinguish its meaning as a threat or a mere nuisance, for example, is crucial for biologic survival--think hearing the sound of a bear approaching in the woods. But among many higher species, hearing is also important for social bonding and interaction--think recognizing different voices or changes in voice patterns and intonation. The exquisitely complex ability to detect changes in intonation begins with the opening of a tiny molecular gate in TMC1.

"We now know that TMC1 forms the pore that enables sound detection in animals ranging from fish to birds to humans," author said. "It is truly the protein that lets us hear."

https://hms.harvard.edu/news/hearing-molecule

https://www.cell.com/neuron/fulltext/S0896-6273(18)30631-7