Aug. 3, 2000 -- To sense what's happening around us, we use our vision, hearing, and sense of touch and smell. But cells also sense and respond to what's happening in their microscopic world. Now, researchers have obtained the first detailed snapshot of a key protein that helps them do it.
The protein and its cousins play key roles in pain relief, depression, blood pressure regulation, vision, smell, taste, and more. As a result, researchers believe that the results could lead to better drugs for a wide variety of disorders. The results were reported by an international team in Friday's issue of the journal Science.
The protein, called rhodopsin, resides in the rod cells of the eye's retina, where it senses light and helps the cells respond by sending a signal to the brain via nerve cells.
Rhodopsin is a member of a large family of proteins called G-protein coupled receptors (GPCRs) that help regulate blood pressure, development of embryos, heart function, hormone responses, moods, pain, and much more, says Philip Yeagle, PhD, professor and head of the department of molecular biology at the University of Connecticut, in Storrs. The detailed new snapshot of rhodopsin is "very important because [GPCRs] control a tremendous variety of cellular functions," he tells WebMD.
To determine the structure of rhodopsin, Krzysztof Palczewski, PhD, and his colleagues from Hyogo, Japan, first isolated the protein from cow retinas. Then, through a lot of trial and error, they found a bath with the precise blend of detergents, salt, and organic molecules to coax the protein to form crystals. Finally, they determined the structure by seeing how X-rays bounce off it.
The result was a snapshot of the protein that was much more in focus than any previous image of a GPCR, Elaine Meng, PhD, tells WebMD. Meng, who coauthored an editorial that accompanied the paper, is a staff researcher in the department of cellular and molecular pharmacology at the University of California, San Francisco.
The new snapshot should help researchers figure out how rod cells respond to light. Light causes a shape change in rhodopsin, which sits on the surface of the cell. That, in turn, triggers a chain reaction that causes the rod cell to send a visual signal to the brain, Palczewski tells WebMD. He is a professor of chemistry, ophthalmology, and pharmacology at the University of Washington in Seattle.
By understanding the details of how rhodopsin works, researchers could design drugs to treat some forms of retinitis pigmentosa, a disorder which leads to night blindness. That's because a mutant form of rhodopsin causes some forms of the disease, and a drug could help the mutant rhodopsin proteins act like normal ones.
But the implications of the results go much further, Yeagle says. Other studies have shown that other GPCRs have a very similar shape to rhodopsin. Using computer modeling based on the clear image of rhodopsin, chemists could design small molecules that nestle into folds of other GPCRs and either turn on or turn off signals sent by the cells.
Drugs that block or activate GPCRs are already used to treat high blood pressure, depression, heart disease, and GPCRs represent about 50% of the drug targets of the pharmaceutical industry, Yeagle adds.
However, the new discovery doesn't answer all the questions about rhodopsin or other GPCRs, Meng says. For example, it doesn't show exactly how the signal flips from the off position to the on position, she says. Still, she says, "it opens a door to more efficient, rational drug design."