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, Boston. 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 California Institute of Technology. His thesis work, with James Hudspeth, focused on mechanical 
transduction 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 min- 
ute 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 those channels that detect sound. 
The sound-activated channels occur in a spe- 
cial type of inner-ear cell called a hair cell. These 
cells are named for a bundle of cilia that extends 
from their top surface and that tilts back and forth 
with each cycle of a sound wave. Moving the cilia 
opens and closes the channels. Over 10 years ago, 
it was found that the ion channels could open 
extremely quickly — in just a few millionths of a 
second — when the bundle was deflected. That 
speed rules out the kind of biochemical chain 
used by receptor cells of the eye and nose. We 
proposed instead that mechanical forces on the 
cilia could pull the channels open directly. 
Others have shown that this was true, and it was 
possible to measure the opening movement of 
channels when force was applied to them. But 
where are the channels, and what pulls on them? 
Other workers, having explored around the 
bundle with a fine electrode, indicated that the 
channels were near the tips of the cilia. This was a 
surprising result, since a lever action of the cilia 
might focus forces near the bases. We have re- 
cently confirmed this, however, by putting a fluo- 
rescent dye inside the cell that reports the entry 
of calcium through the channels. When calcium 
is allowed to enter the cell, the fluorescent signal 
appears first at the tips, showing that the channels 
are there. 
With attention focused on the tips of the cilia, a 
group in England discovered that the tips are 
linked by extremely tiny filaments, just 1 50 nano- 
meters long, which they called tip links. To- 
gether these clues led to a beautifully simple 
theory for the operation of hair cells. Deflecting 
the bundle in one direction would stretch the tip 
links, and they would pull directly on the ion 
channels to open them and let ions into the cell. 
Moving in the other direction would relax the 
links and allow channels to close. However, no 
way to test the theory could be found. 
This past year, we have been able to confirm it. 
We found that removing calcium from the fluid 
around the cilia, for just a few seconds, com- 
pletely eliminated the tip links, as observed with 
either transmission electron microscopy or scan- 
ning electron microscopy. When we tested the 
mechanical sensitivity of the hair cells, by mov- 
ing a single bundle and measuring the electrical 
response of the cells, we found that the same 
treatment eliminated the electrical response in a 
few tenths of a second. A further test indicated 
that the electrical response was lost specifically 
because the mechanical tension on the channels 
was gone. Thus tip links do convey the stimulus 
tension to the ion channels. 
In addition to this transduction mechanism in 
these cells, there is an adaptation mechanism that 
enables them to be sensitive to extremely small 
displacements while retaining an ability to re- 
spond over a large range of stimuli. Hair cells 
have a very narrow range of sensitivity. A deflec- 
tion of about a third of a micrometer — the diame- 
ter of one cilium — is sufficient to open all chan- 
nels. We found some years ago, however, that a 
steady deflection that opens all channels is rap- 
idly followed by the spontaneous closure of 
channels. To reconcile this with the context of 
the tip-links model, one must suppose that clo- 
sure is a consequence of relaxing the tension on 
the channels. A further deflection to stretch the 
tip links does, in fact, reopen channels. Thus 
there seems to be a continuous adjustment sys- 
tem, acting to set the tension on the ion channels. 
Indeed, another group found that the stiffness of 
the bundle relaxed with the same time course as 
adaptation, in keeping with a tension adjustment 
scheme. 
In contrast, experiments from a different group 
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