The proteins that form the permeation pathway of mechanosensory transduction channels in inner ear hair cells have not been definitively identified. Genetic, anatomical, and physiological evidence support a role for sensor protein, transmembrane channel-like protein (TMC) 1, in hair cell sensory transduction, but the molecular function of TMC proteins has been unclear.

In a new study published in Neuron, Harvard Medical School Professor of Otolaryngology Jeffrey Holt, PhD, and colleagues teamed with the lab of David Corey, PhD, at Harvard Medical School. Together, they confirmed TMC1’s essential role in hearing, ending a 40-year quest, and mapped out its working parts.

Working with living hair cells in mice, they made substitutions in 17 amino acids within the TMC1 protein, one at a time, to see which substitutions altered hair cells’ ability to respond to stimuli and allow the flow of ions. Eleven amino acid substitutions altered the influx of ions, and five did so dramatically, reducing ion flow by up to 80 percent. One substitution blocked calcium flow completely, thereby revealing the location of the pore within TMC1 that enables ion influx.

The data provide compelling evidence that TMC1 is a pore-forming component of sensory transduction channels in auditory and vestibular hair cells, which could have implications for reversing hearing loss in the future.

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

Adapted from news release issued by Harvard Medical School and Boston Children's Hospital.