Mechanically Activated Ion Channels 
David P. Corey, Ph.D. — Associate Investigator 
Dr. Corey is also Associate Professor of Neuroscience at Harvard Medical School and Assistant Physiologist 
at Massachusetts General Hospital. He studied physics as an undergraduate at Amherst College, conducted 
research for a year at Harvard Medical School, and then entered the neurobiology program at the Cali- 
fornia Institute of Technology. His thesis work, with A. James Hudspeth, focused on mechanical trans- 
duction in auditory receptor cells. His postdoctoral work with Charles Stevens at Yale Medical School was 
on voltage-sensitive ion channels. 
OUR laboratory is interested in how protein 
channels in cell membranes mediate the 
electrical activity of the brain. Such channels, 
which open and close to regulate the flow of mi- 
nute amounts of electrical current into a cell, are 
intimately involved in the brain's information 
processing. They are important in detecting sen- 
sory signals such as light and sound, in the trans- 
mission of this information from the sense organ 
to the brain, and in communication from one 
brain cell to another. We are focusing primarily 
on ion channels in the sensory receptor cells of 
the inner ear, especially on the mechanism of ac- 
tivation of the channels that detect sound. 
Channels that have been studied in other tis- 
sues are of two broad classes: those that are acti- 
vated by the voltage across the cell membrane, 
and those that are activated by some chemical 
either inside or outside the cell. The channels 
that we study are part of a novel third class. They 
are directly activated by a mechanical stress on 
the channel protein, in this case the stress of a 
sound vibration. 
We are especially concerned with those 
aspects of mechanically sensitive ion channels 
that give them their unique sensitivity. What are 
the cellular structures that convey a stimulus to 
the channel protein, and what stimulus do they 
convey? What is the biochemical nature of the 
external link to the channel? What force on the 
channel protein is required to open it? Are there 
various conformations of the protein that are 
closed or open, and what are the energy differ- 
ences among them? 
From our work and that of others, an attractive 
model has emerged for the way vibration causes a 
tension on the ion channels in cells of the inner 
ear. On the top surface of these cells are cilia that 
rock back and forth with each cycle of a sound 
wave. Tiny filaments, recently found to run be- 
tween the tips of the cilia, may connect directly 
to the channels, such that oscillations of the cilia 
alternately stretch or relax the filaments, opening 
the channels or letting them close. High-speed 
electrical measurements indicate that these chan- 
nels can open within a few millionths of a second 
following a mechanical stimulus. 
Although the essence of this model remains to 
be tested, we have worked on some important 
aspects. We recently confirmed the location of 
the mechanically sensitive channels at the tips of 
the cilia, with dyes that change fluorescence 
when they bind ions coming in through the chan- 
nels. Measurement of the mechanics of the cilia 
by high-resolution videomicroscopy indicates 
that all the channels of a cell receive essentially 
the same stimulus. 
To understand what proteins form the struc- 
tural links, we must first learn what proteins con- 
stitute the cilia. To this end, we developed a 
method for studying the cilia that utilizes their 
adhesion to sticky paper and separation of their 
proteins according to size and electrical charge. 
We have found about 12-18 diff^erent proteins as 
major constituents and have identified several by 
size and their reaction with certain antibodies. 
Much work remains to identify the rest and learn 
their roles. 
In addition to this transduction mechanism, 
there is an adaptation mechanism in these cells 
that renders them sensitive to extremely small dis- 
placements while they respond over a large range 
of stimuli. This seems to work by a continuous 
adjustment system, acting to set the tension on 
the channels. Within a tenth of a second, the sys- 
tem can restore the resting tension, which is 
enough to keep some of the channels open at any 
time. 
Our experiments and those of others suggest 
that the adaptation comes about by a movement 
of the points where the filaments are attached to 
the cilia. When the filaments are stretched to 
open channels, the attachment points slip to al- 
low the fibers to shorten. Conversely, when the 
filaments are relaxed, the attachment points 
climb to stretch them, to restore the resting ten- 
sion on ion channels. The slipping process is ac- 
celerated by the movement of calcium into the 
tips of the cilia, suggesting the mechanism is 
there. Alteration of the calcium changes the rest- 
ing tension set by this motor. It also causes a tiny 
movement of the bundle of cilia — by about 1 
millionth of an inch — which we can observe 
with videomicroscopy. Thus the mechanism 
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