We wouldn’t be able to see, smell, or hear without sensory cells, which convert what’s happening in the world into electrical signals sent to our brains. One of the most delicate kinds of sensory cells lies in our ears. Scientists have known for decades that when activated by sound vibration or head movement, ion channels on the membrane of our inner-ear sensory cells—known as hair cells—will open up a pore, triggering a cascade of signaling events that allow us to hear and keep our balance. But the molecular basis of that pore has remained unclear.
Now, a team led by David Corey of Harvard Medical School and Jeffrey Holt of Boston Children’s Hospital report evidence that a protein called TMC1 forms the pore, allowing ions to flow into the inner-ear hair cells, a critical step in converting sound to electrical signal (Neuron 2018, DOI: 10.1016/j.neuron.2018.07.033).
Karen Avraham of Tel Aviv University, who wasn’t involved with the work but in 2002 found that a TMC1 mutation causes deafness in aptly named Beethoven lab mice, says that research done over the years has suggested TMC1 has an important role in hearing. This latest paper, however, “clinched it.”
By mutating amino acid residues of the TMC1 protein in mice, the researchers could examine whether the change would alter sound-induced electric currents in hair cells isolated from the animals. They substituted each residue with cysteine, then modified each cysteine with a bulky charged group. Almost all residue modifications inhibited the electric currents within seconds, suggesting ion flows were affected by mutations in TMC1 and that TMC1 forms the pore of the ion channel in hair cells.
Avraham says the work has implications for future hearing loss therapies. Understanding the basic mechanisms of how sound vibration is converted into electrical signals could help develop a therapy for not only TMC1-variant-caused deafness, which affects a relatively small number of people, but also all forms of hearing loss, Avraham says. An estimated 400 million people of all ages worldwide experience hearing loss.
Corey says that drug therapies targeting naturally occurring TMC1 mutations in humans could be possible, but initial treatments are more likely to employ gene therapies that replace the mutant protein or directly correct the gene. Because TMC1 only works along with other proteins within hair cells, he explains, screening 10,000 drug candidates might require 10,000 mouse ears, which is not practical. Co-lead author Jeffrey Holt has patents on TMC1 gene therapy and advises biotech companies developing inner-ear therapies.