Fine Regulation of Receptors Achieved
A lot of drugs target the GPC receptors in the body. Photo: Andrea Damm / Pixelio.de
With this diagram, the researchers describe how the newly designed agents work on the receptors. Picture: Institute of Pharmacy and Food Chemistry
A large number of drugs for cardiac insufficiency, high blood pressure and other conditions take effect by modulating the function of receptors. Researchers from Würzburg, Bonn and Milan have now designed new agents, with which receptors can be finely regulated in a completely novel way.
Beta blockers are drugs for high blood pressure. In the organism, they attach themselves to specific receptors that would otherwise bind to the "stress hormone" adrenaline. The blockage of the receptor molecules renders the adrenaline ineffective and the blood pressure drops.
All body cells have a great variety of such receptors on their surface. These are used to receive messages from the environment and to adjust the cell function accordingly. The G protein coupled receptors (GPCR) comprise a large group of receptors. They serve for processing external or internal stimuli, such as odors and flavors or nerve and hormone signals.
Undesirable: one agent sets off several signals
"A lot of our drugs modify the function of specific GPC receptors," says Ulrike Holzgrabe, Professor of Pharmacy at the University of Würzburg. The receptors are activated or deactivated in this process. In case of GPC receptors, however, the "activation" often involves setting off several signals with various meanings within the cell. This can lead to undesirable side effects.
In this field, a team of researchers from Würzburg, Bonn and Milan have now discovered a completely novel approach: They identified an area in the protein structure of a GPCR that can be used as a switch point for signals. Their progress is reported in the prestigious journal "Nature Communications".
Innovative: agents working in a carefully targeted way
What the scientists achieved: With specially designed agents, they are able to activate a certain GPCR, the so-called muscarinic receptor, at a particular point while giving the response signal a specific direction at another point. In this way, the activation does not set off several signals, but only one – the desired one in each case.
"Numerous members of the GPCR family have such switch points in their protein structure so that further receptors should be capable of being regulated in this novel way as well," says Holzgrabe. This opens the prospect of developing innovative drugs which manipulate the cell function in a more targeted way, enabling a more effective and well tolerated treatment. Next, the researchers are going to design further agents in order to get more insights into the signal transduction of GPC receptors.
“The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling”, Andreas Bock, Nicole Merten, Ramona Schrage, Clelia Dallanoce, Julia Bätz, Jessica Klöckner, Jens Schmitz, Carlo Matera, Katharina Simon, Anna Kebig, Lucas Peters, Anke Müller, Jasmin Schrobang-Ley, Christian Tränkle, Carsten Hoffmann, Marco De Amici, Ulrike Holzgrabe, Evi Kostenis & Klaus Mohr, Nature Communications 3, 4. September 2012, DOI 10.1038/ncomms2028
Contact person
Prof. Dr. Ulrike Holzgrabe, Department of Pharmaceutical and Medicinal Chemistry, University of Würzburg, T (0931)85461, 
holzgrab@pharmazie.uni-wuerzburg.de
12.09.2012, 14:22 Uhr