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Medicinal Chemistry

Light-activated molecule triggers neurons for hearing in gerbils

The photoswitchable molecule tethers itself to the auditory nerve and mimics hair cell stimulation in the inner ear

by Alla Katsnelson, special to C&EN
May 19, 2022


A scheme showing a molecule changing shape from trans to cis when hit by blue light. Because the molecule is tethered to a cell's receptor. the shape change causes the end of the molecule, which resembles glutamate, to fall into the receptor.
The multi-segment molecule anchors itself to a neuron’s glutamate receptor and changes shape under blue light. That causes a glutamate ligand (red) to fall into the receptor’s binding site and triggers the neuron to send an auditory signal.

Ear drops containing light-activated molecules may one day help restore hearing in people with some forms of hearing loss. Researchers used such molecules to trigger neurons in the inner ear of gerbils, essentially creating chemical prosthetics for missing or damaged hair cells in the auditory system (J. Am. Chem. Soc. 2022, DOI: 10.1021/jacs.1c12314)

In an intact auditory system, sound-triggered vibrations from the ear drum bend hair cells in the cochlea, a fluid-filled structure in the inner ear that’s shaped like a snail shell. Hair cells tuned to different vibrational frequencies then transform these vibrations into electrical activity, stimulating auditory nerves and sending sound signals to the brain. For the past 50 years, about 1 million people with hearing loss have used devices called cochlear implants to essentially replace damaged hair cells by directly stimulating nerves in the ear with electric pulses. But the resolution of these devices is too low to convey the full spectrum of sound frequencies, and they don’t filter out background noise well.

To create a chemical alternative, physicist Pau Gorostiza of the Institute for Bioengineering of Catalonia, Tobias Moser of the University Medical Center Göttingen, and colleagues designed and synthesized a molecule that plugs into receptors in the chochlea for glutamate, a neurotransmitter that makes the auditory nerve fire. Exposing the molecules to a rapidly flashing blue light activates the receptors which then transmit a signal down the neuron.

The system is a chemical twist on a method devised by Moser’s group a few years ago in which the researchers genetically engineered gerbils to express receptors in the auditory nerve that could be activated by implanted light-emitting diodes. This optogenetic approach offered better frequency resolution than cochlear implants, but genetically manipulating neurons is hard to control, causing light-sensitive receptors to bunch up in the wrong places on the neuron.

The new photoswitchable molecule has two parts linked together through click chemistry: a head made of a glutamate ligand and a light-activated azobenzene group, and a tail that anchors the molecule to the glutamate receptor.

To test the molecule, the researchers infused it into the surgically exposed cochleas of gerbils. The molecule’s tail covalently bonds to the receptor near glutamate’s binding site, positioning the head of the molecule there. When blue light hits the azobenzene group, the molecule twists from its trans form to its cis form and dunks its glutamate head into the binding site, firing the neuron. “It’s like a fishing line, with a hook [that goes] inside the mouth of the receptor,” Gorostiza says.

When the blue light turns off, the molecule relaxes, and the head moves out of the receptor’s binding site, deactivating the neuron. That switch happens as quickly as the auditory system registers sound. The frequencies the gerbils hear depend on where in the cochlea the light is delivered.

“It’s a really nice intersection of a biological or clinical application and something where you can tune the chemistry to achieve what you want,” says Andrew Woolley, a chemical biologist at the University of Toronto.

The researchers are now fiddling with the molecule to make it smaller, easier to synthesize, and more potent. “Probably this compound is not a good drug candidate,” says Gorostiza. “It just demonstrates the approach is possible.”

Other clinical challenges will likely need to be solved, says Matthew Xu-Friedman, a neuroscientist at the University at Buffalo. For example, getting the molecule safely into the inner ear may be difficult. And because these glutamate receptors re-form every day or two, the molecule may have to be frequently applied, he says.


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