Dr. Axel is also Higgins Professor of Biochemis- 
try and Molecular Biophysics and Professor of Pa- 
thology at Columbia University College of Physi- 
cians and Surgeons. 
Articles 
Goulding, E.H., Ngai, J., Kramer, R.H., Colicos, 
S., Axel, R., Siegelbaum, S.A., and Chess, A. 
1992. Molecular cloning and single-channel prop- 
erties of the cyclic nucleotide-gated channel from 
catfish olfactory neurons. Neuron 8:45-58. 
KornerJ., Chun, J., O'Bryan, L., and Axel, R. 1991. 
Prohormone processing in Xenopus oocytes-, char- 
acterization of cleavage signals and cleavage en- 
zymes. Proc Natl Acad Sci USA 88:11393- 
11397. 
Leahy, D.J., Axel, R., and Hendrickson, W.A. 
1992. Crystal structure of a soluble form of the 
human T cell coreceptor CD8 at 2.6 A resolution. 
Ce// 68:1145-1162. 
Robey, E.A., Ramsdell, F., Kioussis, D., Sha, W., 
Loh, D.Y., Axel, R., and Fowlkes, B.J. 1992. The 
level of CD8 expression can determine the out- 
come of thymic selection. Cell 69:1089-1096. 
ACTIVATION AND REGULATION OF ION CHANNELS 
David P. Corey, Ph.D., Associate Investigator 
Dr. Corey's laboratory is interested in the regula- 
tion of membrane permeability in neurons, which 
underlies such processes as sensory transduction, 
membrane excitability, and synaptic transmission. 
The broad goal is to understand the ion channel pro- 
teins that mediate permeability, the mechanism of 
their activation, and the processes of their expres- 
sion and control. 
The special interest of Dr. Corey's group is ion 
channels that are activated by direct mechanical 
stress on the channel protein. Such channels may 
underlie a variety of mechanical sensitivities in dif- 
ferent tissues. In Dr. Corey's laboratory, they are be- 
ing studied specifically in hair cells, the mechani- 
cally sensitive receptor cells of the inner ear that 
transduce sound into an electrical signal. These 
cells bear a bundle of 50-200 cilia on their apical 
surface, and deflection of the bundle by sound 
opens ion channels in the tips, allowing ionic 
current to enter the cell. A long-standing theory for 
transduction is that deflection of the bundle 
stretches fine filaments, or "tip links," that extend 
between the tips of the cilia, and that these pull 
directly on the ion channels to open them. Last year. 
Dr. Corey's group was able to show that tip links do 
pull on the channels, which helps to confirm the 
theory. 
Physiological Limits to Adaptation 
There is also an adaptation mechanism that fol- 
lows displacements. During a maintained positive 
displacement, the transduction current declines 
over tens of milliseconds, which seems to result 
from a relaxation of the tension on channels. Simi- 
larly, a displacement that allows channels to close 
activates a retensioning mechanism that reopens 
channels. Together these act to keep a constant pro- 
portion of channels open. More specifically, the ad- 
justment appears to come about by a movement of 
one end of the elastic element that conveys tension 
to the channel. Work from several laboratories has 
led to the thought that some motor element contin- 
ually tries to increase tension on the channels, but 
slips if the tension becomes too great. 
This year Dr. Corey's laboratory has found that 
this adaptation mechanism only works over a lim- 
ited range. For small deflections (up to ~0.7 ^im in 
either direction, as measured at the bundle's tip), 
the motor successfully adjusts the tension to restore 
the resting level. For larger deflections, however, 
the tension adjustment is incomplete. The motor 
seems to hit a limit of some sort, beyond which it 
cannot move. 
Structural Basis of Adaptation 
The tip-link hypothesis can be combined with the 
adaptation model, by imagining that the motor ele- 
ment moves the upper end of the tip link along the 
side of a stereocilium. The structural correlate of 
adaptation would thus be the movement of the at- 
tachment point. In the past two years. Dr. Corey and 
his colleagues have been testing this view, with 
cells fixed before and after adaptation. The osmio- 
philic densities marking the tip-link attachments 
were observed with electron microscopy. In a quan- 
titative analysis of micrographs, the densities were 
found to move along the sides of stereocilia in the 
direction predicted. When tip links were cut, re- 
lieving tension on the densities, they climbed along 
the stereocilia. On the basis of these observations, 
394 
