G protein-coupled receptors (GPCRs) are key players in cell communication and represent the largest class of drug targets. However, GPCR lead compound development has suffered from a low success rate the last 10 years, likely because these receptors are more complex than initially thought. GPCRs are known to form dimers and higher oligomers with specific properties, but the physiological relevance of this oligomerization remains elusive in native tissues. Deciphering the precise functional consequences of GPCR oligomerization is a major challenge in the field and of primary importance to stimulate further drug development.
The GABAB receptor – the GPCR for the main inhibitory neurotransmitter, GABA – is an excellent model for studying GPCR oligomerization: Not only is it an obligatory heterodimer composed of GABAB1 and GABAB2 subunits, but it was recently demonstrated by the host laboratory that the GABAB receptor can assemble into larger entities through a direct interaction of the GABAB1 subunits, both in transfected cells and in brain membranes. The aims of the present project are to (i) Identify the stoichiometries and dynamic properties of GABAB oligomers at different localizations in primary neurons, (ii) identify the molecular mechanisms that regulate the GABAB oligomer stoichiometry and characterize them in vitro, and (iii) determine the functional significance of the GABAB oligomers. To reach these goals, we will develop innovative microscopy techniques for quantitative analysis of GABAB oligomerization and novel fluorescent tools for labeling of GABAB in neurons in collaboration with a biotech company.
By using state of the art technologies, this study will bring the first clear demonstration of the existence, regulation and functional relevance of GABAB oligomers in native tissue. This will open up new opportunities for development of GABAB modulators for the pharmaceutical industry and methods that could easily be transposed to other membrane receptors.
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