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Stanford researcher’s discovery of ion channel turns ear on its head

Article / Review by on September 23, 2009 – 9:32 pmNo Comments

Stanford researcher’s discovery of ion channel turns ear on its head

STANFORD, Calif. — Scientists thought they had a good model to explain how the inner ear translates vibrations in the air into sounds heard by the brain. Now, based on new research from the Stanford University School of Medicine, it looks like parts of the model are wrong.

Anthony Ricci | Academic Appointments Professor, Otolaryngology (Head and Neck Surgery) |Member, Bio-X | Professor (By courtesy), Molecular & Cellular Physiology Anthony Ricci, PhD, associate professor of otolaryngology, and colleagues at the University of Wisconsin and the Pellegrin Hospital in France found that the ion channels responsible for hearing aren’t located where scientists previously thought. The discovery turns old theories upside down, and it could have major implications for the prevention and treatment of hearing loss.

“I had thought that the channels were in a very different place,” said Peter Gillespie, PhD, professor of otolaryngology at Oregon Health and Science University, who was not involved with the study. “This changes how we look at all sorts of previous data.” The findings will appear in the May issue of Nature Neuroscience.

Ricci explained, “Location is important, because our entire theory of how sound activates these channels depends on it. Now we have to re-evaluate the model that we’ve been showing in textbooks for the last 30 years.”

Deep inside the ear, specialized cells called “hair cells” sense vibrations in the air. The cells contain tiny clumps of hairlike projections, known as stereocilia, which are arranged in rows by height. Sound vibrations cause the stereocilia to bend slightly, and scientists think the movement opens small pores, called ion channels. As positively charged ions rush into the hair cell, mechanical vibrations are converted into an electrochemical signal that the brain interprets as sound.

But after years of searching, scientists still haven’t identified the ion channels responsible for this process. To pinpoint the channels’ location, Ricci and colleagues squirted rat stereocilia with a tiny water jet. As pressure from the water bent the stereocilia, calcium flooded into the hair cells. The researchers used ultrafast, high-resolution imaging to record exactly where calcium first entered the cells. Each point of entry marked an ion channel.

The results were surprising: Instead of being on the tallest rows of stereocilia, like scientists previously thought, Ricci’s team found ion channels only on the middle and shortest rows.

Ion channels on hair cells not only convert mechanical vibrations into signals for the brain, but they also help protect the ear against sounds that are too loud. Through a process called adaptation, the ear adjusts the sensitivity of its ion channels to match the noise level in the environment. Most people are already familiar with this phenomenon, Ricci said, though they might not realize it. “If you watch TV in bed and you have the sound turned down low, you can hear fine when you’re going to sleep,” he said. “But then when you get up in the morning and turn on the news, you have to turn the volume up.”

That’s because at night, when everything is quiet, the ear turns up its amplifier to hear softer sounds. “But when you get up in the morning,” Ricci said, “and the kids are running around and the dog is barking, the ear has to reset its sensitivity so you can hear in noisier conditions without hurting your ear.”

Defects in the ear’s adaptation process put people at risk for both age-related and noise-related hearing loss. Understanding adaptation is a fundamental step in preventing hearing loss, said Robert Jackler, MD, the Edward C. and Amy H. Sewall Professor in Otorhinolaryngology at Stanford.

“Many forms of hearing loss and deafness are due to disturbances in the molecular biology of the hair cell,” said Jackler, who was not involved in the study. “When you understand the nuts and bolts of how the hair cell works, you can understand how it goes wrong and can set about learning how to fix it.”

The study was funded by grants from the National Institute on Deafness and Other Communicative Disorders. Other scientists have attempted similar experiments in the past, but they used less-sensitive imaging techniques. “Our microscope took images at 500 frames per second,” said Ricci, who led the imaging experiments. “That’s much faster than it’s ever been done before.”

Ricci and colleagues also used hair cells from rats, while previous experiments had been done in bullfrogs. Because mammals have fewer, more widely spaced rows of stereocilia, the team was able to determine the precise location of the ion channels.

“They chose their experimental preparation quite wisely,” Gillespie said. “The ear is really hard to get at because it’s a tiny organ, it’s encased in very hard bone and there are very few hair cells.”

But Ricci’s study wasn’t just a triumph in experimental protocol. Millions of Americans suffer from hearing loss and deafness, and until scientists understand the molecular basis of normal hearing, it’s difficult to understand what can go wrong. “We need to know specifically how hearing works,” Ricci said, “or we can’t come up with better treatments.”

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 Anthony Ricci. Bio.
Academic Appointments Professor, Otolaryngology (Head and Neck Surgery)
Member, Bio-X
Professor (By courtesy), Molecular & Cellular Physiology

> Professional EducationPhD: 
Tulane University , Neuroscience (1992) 
BA:  Case Western Reserve University , Chemistry (1985) 

> Postdoctoral Advisees
Manuel Castellano Munoz   Thomas Effertz   Jee-Hyun Kong   Anthony Peng

> Graduate & Fellowship Program
AffiliationsMolecular and Cellular Physiology Neurosciences

> Current Research Interests
The auditory system is a remarkable feat of engineering capable of detecting motion at the atomic level and transmitting this information to the brain with precise timing and fidelity. We use advanced electrophysiologic, imaging, molecular and pharmacologic techniques to probe mechanisms of mechanotransduction and synaptic transmission at the auditory periphery. There are several independent lines of research in the laboratory.

Mechanotransduction, the conversion of mechanical stimulation into an electrical signal, is complex and involves a variety of proteins, many of which have not yet been identified. A major goal of the laboratory is to delineate the functional relevance of mechanotransduction and to identify proteins and their function in this process. To date, we have identified and characterized the tuning properties of the sensory hair bundle and mechanotransducer channels, identifying at least two new physiologically relevant contributions of these channels. We have performed the only single channel study of mechanotransducer channels, demonstrating tonotopic variations in the intrinsic channel properties. We have also performed the only kinetic analysis of activation, again demonstrating tonotopic variations in the kinetics of the mechanotransduction channel. In addition, we have pharmacologically characterized and biophysically mapped the transducer channel pore. Recently we have developed a high speed confocal imaging system that will allow us to optically monitor calcium changes associated with mechanotransduction, allowing us to localize the site of mechanotransduction and directly investigate mechanisms of calcium, regulation.

A second major direction of the laboratory is synaptic transmission where we are interested in identifying mechanisms associated with specializing these synapses to graded and tonic release of transmitter at high rates and with high fidelity. We have morphologically and biophysically characterized these synapses, quantifying…

> Honors and Awards
Burt Evans Young Investigator Award, National Organization for Hearing (2002) Young Investigator Award, Deafness Research Foundation (1999)

 ….

* The Stanford University School of Medicine consistently ranks among the nation’s top 10 medical schools, integrating research, medical education, patient care and community service.  The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital.

**  The above story is adapted from materials provided by Stanford University School of Medicine 

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