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Previously unknown protein subunits of GABAB receptors identified

Neurobiologists from the Universities of Freiburg and Basel have published a report on previously unknown subunits of GABAB receptors of the central nervous system in the renowned scientific journal Nature. GABAB receptors are transmembrane proteins in nerve cells that are of crucial importance for brain function as well as playing a vital role in therapy and pharmaceutics.

Dr. Bernd Fakler © private

A team of scientists led by Prof. Dr. Bernd Fakler from the Institute of Physiology at 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 comprehensively analysing the composition of the brain's GABAB receptors. 

The team identified four new components of the GABAB receptor complexes, including the so-called KCTD proteins, members of a gene family that 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 were not able to reproduce the characteristics of the brain receptors.

Targets for new pharmaceutical substances

It was previously assumed that GABAB receptors are heterodimers consisting of two subunits (red and orange). The new findings show that the known subunits form a tetramer associated with two tetramers of the newly identified KCTD proteins (green, only one KCTD tetramer is visible). Different KCTD proteins influence the activation of effector proteins (G-proteins, blue) and the pharmacological properties of the receptor complex in different ways. © University of Freiburg

GABA (= gamma-amino-butyric acid) receptors are the most important inhibitory neurotransmitter receptors of the central nervous system. They prevent the nerve cells from activating too strongly, and potentially leading to neurological and psychiatric illnesses such as convulsions, depression or anxiety. Two types of GABA receptors, the GABAA and GABAB receptors, are currently known. The GABAA receptors are responsible for rapid inhibition in the brain and are the main site of action of important drugs such as Valium, which is used to treat anxiety conditions, for the therapy of epileptic seizures and as a sleeping aid. GABAB receptors are important for the prolonged inhibition of the nerve cells. Drugs that activate GABAB receptors are used to treat spinal cord injuries, multiple sclerosis, addiction and narcolepsy.

The findings published in "Nature" could have enormous therapeutic benefits. Scientists believe that it will soon be possible to develop drugs that selectively influence a particular receptor subtype. This could lead to a reduction in side effects as well as entirely new therapeutic applications.

In addition to these applications, there is another reason why the research carried out by the physiologists in Freiburg and Basel is of major 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 play a key role in medicine: Approximately 60 per cent of all prescription drugs currently on the market act on these receptors.

The discovery that the structure of GPCRs is both more complex than previously believed and that they include additional specific subunits which have a decisive influence on their signal transduction could greatly increase the number of different GPCR types, and the number of possible drug target proteins.

Publication:
Nature: Native GABAB receptors are heteromultimers with a family of auxiliary subunits.
Jochen Schwenk, Michaela Metz, Gerd Zolles, Rostislav Turecek, Thorsten Fritzius, Wolfgang Bildl, Etsuko Tarusawa, Akos Kulik, Andreas Unger, Klara Ivankova, Riad Seddik, Jim Y. Tiao, Mathieu Rajalu, Johana Trojanova, Volker Rohde, Martin Gassmann, Uwe Schulte, Bernd Fakler, Bernhard Bettler
Published online: 18. April 2010, doi:10.1038/nature08964

Contact:
Prof. Dr. Bernd Fakler
University of Freiburg
Institute of Physiology and Centre for Biological Signalling Studies (bioss) 
Tel.: +49 (0)761 203 5175
E-mail: bernd.fakler(at)physiologie.uni-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/previously-unknown-protein-subunits-of-gabab-receptors-identified