In the latest issue of the renowned scientific journal "Nature" researchers from the universities of Freiburg and Basel report on their discovery of previously unknown subunits of the GABAB receptors in the central nervous system. GABAB receptors are transmembrane proteins in nerve cells which are of fundamental significance for the functioning of the brain and have great therapeutical and pharmaceutical importance. A team of scientists led by Prof. Dr. Bernd Fakler from the Institute of Physiology of the University of Freiburg and the Centre for Biological Signalling Studies BIOSS and Prof. Dr. Bernhard Bettler from the Department of Biomedicine of the University of Basel succeeded in conducting a comprehensive analysis of the composition of the brain’s GABAB receptors.
In the process the team identified four new components of the GABAB receptor complexes: the so-called KCTD proteins, members of a gene family which has not yet been described. The researchers were able to demonstrate that the KCTD proteins determine both the pharmacological and the biophysical characteristics of the GABAB receptors. Among other things, the newly identified proteins explain why the previously known subunits could not reproduce the characteristics of the brain receptors.
GABA (= gamma-amino-butyric acid) receptors are the most important inhibitory neurotransmitter receptors of the central nervous system. They prevent the nerve cells from overly strong activation, which can lead to neurological and psychiatric illnesses such as convulsions, depression, or anxiety. There are currently two known types of GABA receptors, the GABAA and GABAB receptors. GABAA receptors are responsible for rapid inhibition of the brain and are the main site of action of important drugs like valium, which is used to treat anxiety conditions, in the therapy of epileptic seizures, and as a sleeping aid. GABAB receptors are important for more long-term inhibition of the nerve cells. Drugs which activate GABAB receptors are used to treat spinal cord injuries and multiple sclerosis as well as in therapies for addiction and narcolepsy.
The findings published in "Nature" could be of great therapeutical use. Scientists believe that it will soon be possible to develop drugs which selectively influence a particular subtype of receptor. The advantages of such drugs could include a reduction in side effects as well as entirely new therapeutic applications.
In addition to these applications, there is another reason why the research of the physiologists in Freiburg and Basel is of great interest for the pharmaceutical industry: GABAB receptors belong to the family of G-protein coupled receptors (GPCRs), the largest and most diverse group of membrane receptors. GPCRs are a crucial factor for many common drugs: Approximately 60 of all prescription drugs currently on the market act on these receptors. The discovery that the structure of GPCRs is more complex than previously thought and that they include additional specific subunits which have decisive influence on their signal transduction could greatly increase the amount of different types of GPCRs, and thus also of possible target proteins for drugs.
Nature: Native GABAB receptors are heteromultimers with a family of auxiliary subunits.
Jochen Schwenk1, Michaela Metz2, Gerd Zolles1, Rostislav Turecek2,6, Thorsten Fritzius2, Wolfgang Bildl1, Etsuko Tarusawa4, Akos Kulik4, Andreas Unger4, Klara Ivankova2, Riad Seddik2, Jim Y. Tiao2, Mathieu Rajalu2, Johana Trojanova6, Volker Rohde3, Martin Gassmann2, Uwe Schulte1,3, Bernd Fakler1,5, Bernhard Bettler2
Published online: 18 April 2010, doi:10.1038/nature08964
1 Institute of Physiology II, University of Freiburg, Engesserstr. 4, 79108 Freiburg, Germany
2 Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland
3 Logopharm GmbH, Engesserstr. 4, 79108 Freiburg, Germany
4 Institute of Anatomy and Cell Biology, University of Freiburg, Albertstr. 23, 79104 Freiburg, Germany
5 Centre for Biological Signalling Studies (bioss), Albertstr. 10, 79104 Freiburg, Germany
6 Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14220-Prague 4, Czech Republic
Prof. Dr. Bernd Fakler
Institute of Physiology and Centre for Biological Signalling Studies (bioss)
University of Freiburg