Philipp Lachenmann: DELPHI Rationale


G-Protein-Coupled Receptors - Talented All-rounders in Drug

Prof. Hartmut Michel, Max Planck Institute of Biophysics, Frankfurt/Main
Prof. Richard Horuk, Department of Immunology, Berlex, USA

Berlin, Mai 10-12, 2006

Since the early seventies, researchers have been interested in G-protein-coupled receptors—so-called GPCRs. The Ernst Schering Foundation invited experts from around the world to a scientific workshop in Berlin from May 10 to 12, 2006, to talk about the latest trends and findings in GPCR research. The title of this second event as part of the "Scientific Symposia 2006" series organized by the Ernst Schering Foundation was "GPCRs: From Deorphanization to Lead Structure Identification."

GPCRs are membrane receptors responsible for the signal transduction of stimuli as different as light, smell, and taste. The human genome contains around 750 GPCRs. More than half of them are receptors for smell or taste. However, hormones, neurotransmitters, chemokines of the immune system, small chemical molecules, and even viruses can act on GPCRs. Thus, GPCRs are a prime site of action for a large number of drugs.

But not only human signaling factors and therapeutic drugs bind to G-protein-coupled receptors. Opiates like opium and heroin as well as the recreational drug cannabis act upon them. The mechanisms of action of these drugs are mostly known. However, some of the phenomena and side effects observed when taking certain drugs are still unexplained. Professor Graeme Milligan from the University of Glasgow, Scotland, and his research team found the scientific explanation for the so called "munchies," which people frequently experience after smoking cannabis. Professor Milligan reported at the symposium that the G-protein-coupled receptors orexin 1-receptor and cannabinoid1-receptor form a natural pair—a so-called dimer. The orexin1-receptor occurs in areas of the brain associated with the regulation of food intake. "The pairing with the cannabinoid-receptor could explains why people get the munchies after smoking cannabis," said Milligan. "A drug that would target these two receptors could be used as an appetite suppressant as well as to treat cocaine addicts, who suffer from strong cravings." The main news for the scientists at the symposium however was the proof of functional GPCR dimers. The idea that such dimers exist has been discussed since the late nineties, however finding actual proof for their existence has been extremely difficult.

The many ups and downs in GPCR research were illustrated by one of the pioneers in GPCR research, professor Henry Bourne from the University of California, San Francisco. One of the main differences between then and now is the lively discussions between scientists today. "Back in those days people essentially did not talk to each other. We all sat in our labs and offices, having no clue as to what others did in the same field of research," Professor Bourne reported in his keynote lecture. Today large research groups, interdisciplinary projects and a high degree of connectivity between laboratories are found in this area of science. Scientists from industry and academia are able to meet in a relaxed atmosphere, such as the one at this symposium organized by the Ernst Schering Foundation. "Small meetings like this one are very fruitful for the individual scientist," said professor Hartmut Michel, head of the Max Planck Institute of Biophysics in Frankfurt, Germany, Nobel laureate and co-organizer of the symposium. "Small events like this one give you the opportunity to talk to almost everyone present. This leads to new perspectives and creates new ideas for ones own research," said professor Michel.

One of the hot topics in GPCR research is that of viral GPCRs. For the better part of three years, professor Rob Leurs from the Leiden/Amsterdam Center for Drug Research and his team have been trying to uncover some of the mysteries surrounding viruses and G-protein-coupled receptors. This is what they found so far: There are three different types of viruses. The first are those that use human GPCRs to enter cells, i.e. the HI-Virus. Secondly, we find the viruses that reprogram human GPCRs to serve their needs, like the cytomegalovirus, thus suppressing natural immune responses of the body. A third type of virus comes with its own set of human-like GPCRs. These are expressed by the infected cells and can subsequently trigger severe diseases. Professor Leurs was able to show that tumors of the skin cancer Kaposi´s sarcoma, which occurs in patients with AIDS, are in fact caused by the viral oncogene US28, a GPCR of the human herpes virus. "Knowing that viruses can cause or progress certain diseases and cancers will now allow us to develop specific drugs targeting these viruses so that cancer treatment will become more effective," Prof. Leurs said at the symposium.

Further topics at the workshop were signaling of GPCRs inside the cells, identification of functions of the remaining 160 orphan-GPCRs—receptors where one is only aware of their existence—as well as the development of screening assays and high throughput techniques to identify natural or synthetic ligands for drug discovery programs. In many areas of this field of research, scientists are only beginning to understand the underlying mechanisms of these complex receptor proteins. The one thing everybody is eagerly awaiting though is the release of new three-dimensional crystal structures for a receptor, since bovine rhodopsin is the only GPCR crystallized to date. "As it often is the case in science, we are not able to predict when this might be," said professor Hartmut Michel, who has been working on GPCR structures since the late eighties. "But nowadays, new results are possible every day," professor Bourne from San Francisco added.

The results of the symposium will be published by the Springer publishing house and will be available through bookstores. The "Scientific Symposia" series of the Ernst Schering Foundation will continue on August 31–September 1, 2006, with a workshop on "New Avenues to Efficient Chemical Synthesis—Emerging Technologies."


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