Ending a 40-year quest, scientists reveal the identity of 'hearing' protein

August 22, 2018, Harvard Medical School
The snail-shell-shaped part of the inner ear that houses hair cells. Credit: Holt lab/Harvard Medical School

Scientists at Harvard Medical School 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 Aug. 22 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 David Corey, co-senior author on the study and the Bertarelli Professor of Translational Medical Science at Harvard Medical School.

"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 co-senior author Jeffrey Holt, Harvard Medical School professor of otolaryngology and of neurology at Boston Children's Hospital. "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.

"To design optimal treatments for , we need to know the molecules and their structures where disease-causing malfunctions arise, and our findings are an important step in that direction," Holt said.

Credit: Harvard Medical School

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.

As far back as the 19th century, scientists knew that cells located in the inner ear—called for the bristle-like tufts that line their surface—played a role in hearing. The stage was set in the late 1800s by Swedish physician and anatomist Gustaf Retzius, who described in detail the structure and cellular makeup of the inner ear.

The basics of signal propagation from the inner ear to the brain were elucidated in the 1970s. Scientists demonstrated that proteins in the membranes of hair cells could open, allowing the influx of electrically charged ions such as calcium and potassium. Once inside the cell, those ions initiate signal transmission to the brain.

Following the 2002 discovery of the TMC1 gene, research into its role languished for nearly a decade. In 2011, a team led by Holt demonstrated that TMC1 was required for auditory transduction in hair cells. The finding sparked a vigorous debate about the exact role TMC1 played: Was it a central character or part of the supporting cast? That debate has now been put to rest, Holt said.

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.

Engravings showing the structure of the human inner ear by Gustaf Retzius, 1884. Credit: David Corey, Harvard Medical School

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 —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.

This approach, Corey said, was akin to what an engineer might do to figure out how each part of an engine works.

"Hair cells, like car engines, are complex machines that need to be studied as they are running," Corey said. "You can't figure out how a piston or a spark plug works by itself. You have to modify the part, put it back in the engine and then gauge its effect on performance."

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," Holt 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," Corey said. "It is truly the protein that lets us hear."

Explore further: Cellular channels vital for hearing identified

Related Stories

Cellular channels vital for hearing identified

July 18, 2013
Ending a 30-year search by scientists, researchers at Boston Children's Hospital have identified two proteins in the inner ear that are critical for hearing, which, when damaged by genetic mutations, cause a form of delayed, ...

Gene therapy restores hearing in deaf mice

July 8, 2015
Using gene therapy, researchers at Boston Children's Hospital and Harvard Medical School have restored hearing in mice with a genetic form of deafness. Their work, published online July 8 by the journal Science Translational ...

Researchers identify key proteins of inner ear transduction channel

November 21, 2011
National Institutes of Health-funded researchers have identified two proteins that may be the key components of the long-sought after mechanotransduction channel in the inner ear—the place where the mechanical stimulation ...

CRISPR treatment prevents hearing loss in mice

December 20, 2017
Using molecular scissors wrapped in a greasy delivery package, researchers have disrupted a gene variant that leads to deafness in mice.

New research identifies key mechanism behind some deafness

June 29, 2017
Although the basic outlines of human hearing have been known for years - sensory cells in the inner ear turn sound waves into the electrical signals that the brain understands as sound - the molecular details have remained ...

Organization of cells in the inner ear enables the sense and sensitivity of hearing

May 14, 2018
The loss of tiny cells in the inner ear, known as "hair cells," is a leading cause of hearing loss, a public health problem affecting at least one out of three people over the age of 65. Of the two varieties of hair cells, ...

Recommended for you

Research shows signalling mechanism in the brain shapes social aggression

October 19, 2018
Duke-NUS researchers have discovered that a growth factor protein, called brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TrkB) affects social dominance in mice. The research has ...

Good spatial memory? You're likely to be good at identifying smells too

October 19, 2018
People who have better spatial memory are also better at identifying odors, according to a study published this week in Nature Communications. The study builds on a recent theory that the main reason that a sense of smell ...

How clutch molecules enable neuron migration

October 19, 2018
The brain can discriminate over 1 trillion odors. Once entering the nose, odor-related molecules activate olfactory neurons. Neuron signals first accumulate at the olfactory bulb before being passed on to activate the appropriate ...

Scientists discover the region of the brain that registers excitement over a preferred food option

October 19, 2018
At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected ...

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

Brain cells called astrocytes have unexpected role in brain 'plasticity'

October 18, 2018
When we're born, our brains have a great deal of flexibility. Having this flexibility to grow and change gives the immature brain the ability to adapt to new experiences and organize its interconnecting web of neural circuits. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.