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4/23/2009

Is protein camaraderie key to hearing sensitivity?
Rice, BCM explore nanoscale biophysics of key hearing protein

BY JADE BOYD
Rice News staff

The Three Musketeers' motto, "All for one, one for all," may also apply to one of the key proteins in the ear. "Prestin" helps amplify faint sounds and increase the ability to hear tones, and like the musketeers, prestin appears to work best in small groups. Thanks to a new $1.75 million grant from the National Institutes of Health (NIH), scientists from Rice University and Baylor College of Medicine (BCM) are teaming up to unlock the keys to prestin's camaraderie.

"Prestin was discovered less than 10 years ago, and there's a lot we still don't know about it," said Rob Raphael, associate professor in bioengineering at Rice University. "Prestin responds to changes in electrical potential by changing its shape. The big question is, 'What is the molecular mechanism underlying this unique activity?'"

	Fluorescent markers reveal prestin, a key protein in the ear that expands and contracts in response to electrical signals.

Prestin, which is named for the fast musical tempo presto, is found in the outer hair cells of the cochlea, the hearing organ found deep inside the ear. Prestin is a transmembrane protein, which means it pokes through and is embedded in the outer covering of cells. And like many other transmembrane proteins, evidence suggests that prestin only becomes fully functional when it oligomerizes, or comes together in small groups.

"We want to understand the molecular interactions that glue prestin molecules together so they can function efficiently," Raphael said.

He is working with BCM molecular neuroscientist Fred Pereira on a new five-year grant from the NIH's National Institute on Deafness and Other Communication Disorders to investigate the molecular interactions that are responsible for prestin's electromechanical activity. Using sophisticated optical imaging and electrophysiological techniques, Raphael's group will study how prestin responds to electrical stimulation and how membrane dynamics are altered when prestin is both by itself and in groups. Pereira's group will use molecular techniques to mutate regions of the protein to determine which portions of the protein make prestin stick together and which are vital to its function.

Prestin is one of the only proteins known to be "piezoelectric." That means that like inorganic piezoelectric crystals, which are commonly used in quartz watches and other devices, prestin both deforms in response to electrical signals and emits electrical signals when its shape changes.

"We want to characterize prestin's functional unit and learn how it works to enable this remarkable and unique electromotile activity," Pereira said.

When sounds reach the liquid-filled cochlea -- the ear's built-in amplifier -- they pulse through the tunnels of the snail-shaped organ, bending tiny hair-like microvilli that energize a specialized type of cell found only in the cochlea, the outer hair cells. When energized, outer hair cells stimulate millions of prestin proteins to lengthen and shorten in a rapid-fire succession. The resulting movement of the entire outer hair cell, in turn, selectively amplifies sound frequencies, allowing the listener to perceive faint sounds that would otherwise be missed.

"Prestin is supposed to be a piezoelectric molecule, but prior studies have been limited to studying prestin’s electrical activity by measuring how it changes membrane capacitance," Raphael said. "Nobody has investigated the corresponding mechanical deformation at the molecular level and observed the hypothesized nanoscale motions that occur when prestin is stimulated by voltage. We're going to do that in a very systematic way."

Unlocking prestin's secrets could help answer key questions about human hearing and the causes of hearing loss and deafness. For example, it's well-known that loud noise exposure and high doses of some drugs, including aspirin, cause temporary deafness. Loud noise exposure increases the levels of free radicals in the cochlea, and free radicals are known to react with lipid compounds that make up the cell membranes that surround and support prestin. High doses of some drugs, like aspirin, are also known to weaken these membranes. If prestin indeed works in groups inside the membranes, then the deafness may result because the groups can't form or are prematurely dispersed. That, in turn, could provide clues about the mechanisms of age-related hearing loss and other forms of deafness.

"An additional significance of this research is that prestin is a member of a family of highly conserved membrane transport proteins that are found in other parts of the body,” Raphael said. "Mutated forms of the proteins in this family have been implicated in various diseases. So what we learn about prestin in hearing will also have relevance for understanding the molecular basis of a range of other diseases, including skeletal abnormalities in dwarfism, congenital chloride diarrhea and goiter."