Finding how water channels - aquaporins - open and close may lead to new drugs

Living organisms are dependent on being able to adjust the water content in their cells. This is achieved by regulating the flow of water through the cell membrane.

Water is ‘turned on’ and ‘turned off’ by membrane proteins that function as water conduits and are called aquaporins. In the new issue of Nature, Professor Per Kjellbom and Associate Professor Urban Johanson, plant biochemists at Lund University, Sweden, describe how this takes place. The discovery is not only a breakthrough for pure science. It may also pave the way for a new type of drug and for new cosmetic products.

Peter Agre discovered the first aquaporin in 1992 in red blood cells and was awarded the 2003 Nobel Prize. Since then, 13 variants of aquaporin have been found in animals and humans and 35 in plants. There are thousands of these aquaporins in every cell membrane. Aquaporins contain a conduit that is so tiny that only a single water molecule at a time can pass through it. But this traffic can be lively indeed. In one second, several billion water molecules can get through. The direction of this water flow is contingent on the osmotic pressure. The water moves in a direction away from a low and toward a high concentration of salt and nutritional substances. But the conduit isn’t always open. The Lund scientists have found out how it opens and closes. This was done in collaboration with a team at Chalmers University of Technology in Göteborg, Sweden, under the direction of Richard Neutze, and with Emad Tajkhorshid at the University of Illinois.

“We have used yeast fungi to produce aquaporins,” says Per Kjellbom. With our method we can produce sufficient amounts of pure aquaporins to obtain the crystals needed for our analyses. It turns out that with the technology we used to crystallize aquaporins they were in the closed position. Previously it had only been possible to produce open aquaporins. This gave us an opportunity to compare open and closed aquaporins and to understand how this opening and closing works at the molecular level.

Even though there are different variants of aquaporin, they are all similar and work in largely the same way. They exist in every living organism, from bacteria to plants, animals, and humans and haven’t changed much in their evolution. The use of the regulatory mechanism has been patented. A newly established company is going to design new drugs and produce plants that are resistant to drought. Per Kjellbom gives a few examples:

“The kidneys are responsible for maintaining a water balance in the body. If we can identify a chemical compound that can close the aquaporins in the kidneys, this can be developed into a diuretic drug. By the same token, compounds that stabilize the closed structure could be used in cancer treatment. Open aquaporins are necessary for cells to be able to move and form new blood vessels, which tumors are very dependent on to grow. By closing these aquaporins, tumor growth and metastases could be inhibited. There are also a number of genetically inherited diseases that disturb the water balance in the body. The moisture balance in the skin is dependent on aquaporins, a fact that is used both in drugs and cosmetic products. These include antiperspirants and moisture-conserving skin creams to counteract aging.”

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