Thursday, January 27, 2005

ClockNews #17: Melanopsin

Melanopsin plays a key role in the inner workings of the eye

A Brown University team has found that a protein called
melanopsin plays a key role in the inner workings of mysterious, spidery cells
in the eye called intrinsically photosensitive retinal ganglion cells, or
ipRGCs. Melanopsin, they found, absorbs light and triggers a biochemical cascade
that allows the cells to signal the brain about brightness. Through these
signals, ipRGCs synchronize the body’s daily rhythms to the rising and setting
of the sun. This circadian rhythm controls alertness, sleep, hormone production,
body temperature and organ function. Brown researchers, led by neuroscientist
David Berson, announced the discovery of ipRGCs in 2002. Their work was
astonishing: Rods and cones aren’t the only light-sensitive eye cells. Like rods
and cones, ipRGCs turn light energy into electrical signals. But while rods and
cones aid sight by detecting objects, colors and movement, ipRGCs gauge overall
light intensity. Numbering only about 1,000 to 2,000 out of millions of eyes
cells, ipRGCs are different in another way: They have a direct link to brain,
sending a message to the tiny region that controls the body clock about how
light or dark the environment is. The cells are also responsible for narrowing
the pupil of the eye. "It’s a general brightness detection system in the eye,"
said Berson, the Sidney A. Fox and Dorothea Doctors Fox Professor of
Ophthalmology and Visual Sciences. "What we’ve done now is provide more details
about how this system works." The research, published in the current issue of
Nature, provides the first evidence that melanopsin is a functional sensory
photopigment. In other words, this protein absorbs light and sets off a chain of
chemical reactions in a cell that triggers an electrical response. The study
also showed that melanopsin plays this role in ganglion-cell photoreceptors,
helping them send a powerful signal to the brain that it is day or night. The
team made the discovery by inserting melanopsin into cells taken from the
kidneys and grown in culture. These cells, which are not normally sensitive to
light, were transformed into photoreceptors when flooded with melanopsin. In
fact, the kidney cells responded to light almost exactly the way ipRGCs do,
confirming that melanopsin is the photopigment for ganglion-cell photoreceptors.
"This resolves a key question about the function of these cells," Berson said.
"And so little is known about them, anything we learn is important." Berson and
his team made another intriguing finding: The biochemical cascade sparked by
melanopsin is closer to that of eye cells in invertebrates like fruit flies and
squid than in spined animals such as mice, monkeys or humans. "The results may
well tell us that this is an extremely ancient system in terms of evolution,"
Berson said. "We may have a bit of the invertebrate in our eyes." The research
team from Brown included lead author and post-doctoral research associate Xudong
Qiu and post-doctoral research associate Kwoon Wong, both in the Department of
Neuroscience, as well as graduate students Stephanie Carlson and Vanitha Krishna
in the Neuroscience Graduate Program. Tida Kumbalasiri and Ignacio Provencio
from the Uniformed Services University of the Health Sciences also contributed
to the research.

Ha, strike one for melanopsin! This is one of the ongoing big battles in chronobiology. On one side is the Melanopsin "mafia", led by Foster, Provencio and Berson. Their strategy is to show that melanopsin is the only photopigment involved in circadian photoentrainment and completely ignore the existence of other pigments.

On the other hand, there is the opposing Cryptochrome "mafia" (Sankar, Ruby, van Gelder) whose tactic is not just to show that cryptochrome is the pigment, but also that melanopsin is not. Both sides have some very strong and some very fishy data to show.

Of course, there is the third group, the sophisticates led by Mrosovsky who realize that a complex, and somewhat redundant system is what should be expected from evolutionary theory in the first place. They, just to make a point, produce great data demonstrating that yes, classical rods and cones (wit htheir pigments rhodopsin and color-opsins) also play a role in entrainment.

With each pigment tuned to a different wavelength of light, and the spectral composition of natural light changing over the course of the day, isn't it reasonable to expect that a finely tuned photodetection system would be able to track such changes in the environment?

Anyway, what is exciting about this study is the ancient origin of the signaling cascade, something that has been semi-expected by the field, as circadain photoreception is an older function for photoreception than vision.

The next big question: are deep-brain extraretinal photoreceptors in birds, reptiles, amphibians and fish also ancient? How about their pineal and parapineal (frontal organ) photoreceptors? What photopigments and transduction signalling cascades are involved?

...and there's more:

Cells see the light with melanopsin

Thanks to the rod and cone cells in our eyes, our
brains can use light to build images. Recent studies identified a third type of
cell that responds to light and dark. Three research groups have now confirmed
that melanopsin is the pigment that this cell-type uses, opening possible
avenues for treating blind people.
In the classic model, mammals have two
types of light-detecting cells, called photoreceptors, in the retina at the back
of their eye. Rod cells use the rhodopsin pigment to pick up dim light, and cone
cells use related pigments to discriminate colour.
But three years ago,
scientists found a third type of light-sensitive cell. In such cells, a pigment
called melanopsin is used to tell night from day. But apparently the visual
parts of the brain do not use this information. Instead, these cells communicate
with the neurons at the base of the brain that set the daily body cycle.
example, mice without working rods or cones cannot see images. But researchers
showed that they can still use a small set of melanopsin-containing cells in the
retina to adjust their biological clocks. Exactly how melanopsin worked,
however, remained a mystery.
Convincing conversion
Now researchers have
proved that melanopsin is a light-sensitive pigment, by activating the gene for
it inside non-vision cells, and converting them into photoreceptors. The results
of their work appear this week in the journals Science1 and Nature2,3.
Previous studies had shown that a small number of ganglion cells need
melanopsin to respond to light. "But that doesn't prove it's a photopigment, it
just shows that it's crucial," says neuroscientist Mark Hankins of Imperial
College in London.
By making embryonic mouse neurons produce melanopsin, he
and his team made them sensitive to light. "This shows that it's melanopsin that
functions as a photopigment," says Hankins.
Likewise, another group
demonstrated that frog eggs also became light-sensitive when injected with the
genes for melanopsin. The third team converted human embryonic kidney cells
using this pigment.
"It was fantastic," says Satchidananda Panda, a
biologist at the Salk Institute for Biological Studies in La Jolla, California,
who investigated the frog eggs. He explains that very few light-sensitive
proteins still work in the cells of different species.
Melanopsin resembles pigments in invertebrates' eyes, in that light makes
the cells containing it more active. Pigments in vertebrates' rods and cones
have the opposite effect, inhibiting their cells. This may help biologists
understand the evolution of the circadian rhythm system in humans, says Panda.
The results also underline the possibility of conferring visual powers on
unlikely cells. "If you could put the melanopsin gene into cells then you could
make the normally non-sensitive ones become light-sensitive," says Ron Douglas,
a vision researcher at City University in London.
"It's quite important,
because there are some forms of blindness where the rods and cones are lost,"
says Hankins. In the future, converting other cells in these people's eyes with
melanopsin could help them to form images.


1. Panda,
S. et al. Science 307, 600-604 doi:10.1126/science.1105121 (2005).
Melyan, Z. et al. Nature advanced online publication doi:10.1038/nature03344
3. Qiu, X. et al. Nature advanced online publication
doi:10.1038/nature03345 (2005).


Another excellent review of the work:
Opsin mediates circadian clock

...and one that is designed to catch the eye and to appeal to the non-scientists and ends up being naively over-optimistic:
Genetic discovery could help restore sight to the blind



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