Mechanism of Phototransduction in Retinal 
Rods and Cones 
King-Wai Yau, Ph.D. — Investigator 
Dr. Yau is also Professor of Neuroscience at the Johns Hopkins University School of Medicine. He received 
an A.B. degree in physics from Princeton University and a Ph.D. degree in neurobiology from Harvard 
University. He did postdoctoral research at Stanford University with Denis Baylor and at Cambridge Uni- 
versity, England, with Alan Hodgkin. For six years thereafter, he was on the faculty at the Department of 
Physiology and Biophysics of the University of Texas Medical Branch at Galveston. He has received the 
Rank Prize in Optoelectronics from the Rank Prize Funds, England. 
VISION begins in the rods and cones of the 
retina, where light is absorbed and trans- 
duced into a neural signal consisting of an elec- 
trical hyperpolarization at the photoreceptor 
membrane. This signal is relayed to second-order 
neurons in the retina through a modulation of the 
release of synaptic transmitter at the photorecep- 
tor's terminal. In darkness the transmitter is re- 
leased at a high rate, and in light the membrane 
hyperpolarization reduces the release in a graded 
fashion. This modulation of synaptic transmitter 
release can lead to a hyperpolarizing or depolar- 
izing response to light in a second-order neuron, 
depending on the polarity of a given synapse. 
The phototransduction process — the way the 
hyperpolarizing response to light is generated in 
the receptors — is as follows. In darkness an ionic 
conductance in the plasma membrane of the re- 
ceptor's outer segment (the part of the cell that 
contains the visual pigment) is kept open by the 
cyclic nucleotide guanosine 3':5'-cyclic mono- 
phosphate (cGMP), letting both Na^ and Ca^^ 
into the cell. This "dark" current depolarizes the 
cell and causes the steady release of synaptic 
transmitter described above. 
Light activates the following reaction cascade: 
light -*■ photoisomerization of visual pigment 
G protein activation cGMP phosphodiesterase 
stimulation cGMP hydrolysis. As a result, the 
cGMP level falls in the outer segment, causing 
the ionic conductance to close and leading se- 
quentially to the membrane hyperpolarization 
and the reduction of synaptic transmitter release. 
This phototransduction scheme applies to both 
rods and cones, with only quantitative differ- 
ences between the two types of receptors. 
One consequence of the conductance closure 
in the light is that the Ca^^ influx stops. The re- 
sulting imbalance between influx and efflux 
leads to a decrease in the intracellular free Ca^"^ 
concentration. This Ca^"^ decrease reduces a tonic 
inhibition exerted by Ca^^ on the cGMP-synthe- 
sizing enzyme guanylate cyclase and causes an 
increase in the synthesis of cGMP in the light. 
Thus Ca^^ mediates a negative feedback on the 
light-activated cGMP hydrolysis, and this feed- 
back should be a candidate mechanism underly- 
ing the well-known phenomenon of background 
light adaptation in photoreceptors. Indeed, we 
have found that this adaptation essentially disap- 
pears upon removing the feedback experimen- 
tally by eliminating the Ca^^ influx and efflux. 
We have now gone on to ask the complemen- 
tary question — whether we can quantitatively 
predict the background adaptation in photore- 
ceptors from the known properties of the Ca^"*^ 
feedback. First, we derived the time course of 
light-induced phosphodiesterase activity (which 
hydrolyzes cGMP) from a cell's response to a dim 
flash in the condition of no feedback. Next, we 
introduced the equations that describe the Ca^^ 
feedback, the components of which include a 
Ca^^ influx through the cGMP-gated conduc- 
tance, a Ca^"^ efflux through a Na^-Ca^^ exchange 
mechanism, and the Ca^"^ modulation on the 
guanylate cyclase. All of these processes are 
known in quantitative detail from previous work. 
Computations showed that such a simple 
model of the Ca^"^ feedback could indeed predict 
quite well a cell's physiological response to a 
dim flash. Furthermore, the model led to a 
steady-state response-intensity relation for steps 
of light that also fitted well the experimental re- 
lation. The predicted response-intensity relation 
is consistent with Weber's law, which constitutes 
the classical description of background light ad- 
aptation. In summary, there is both experimental 
and theoretical support for the Ca^"^ feedback to 
be the predominant mechanism underlying back- 
ground adaptation in photoreceptors. 
Another problem we are working on is a molec- 
ular characterization of the cGMP-activated con- 
ductance mediating phototransduction. This 
conductance now appears to belong to a family of 
cyclic nucleotide-gated channels that includes a 
channel in olfactory cilia supposedly mediating 
olfactory transduction. The known channels in 
this family so far are all slightly diff^erent from one 
another in their functional characteristics. For ex- 
ample, the rod and cone channels show similar 
activation by cGMP but differ in the current- 
voltage relation. The olfactory channel, on the 
other hand, diff'ers from both the rod and cone 
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