For over two decades the hypothesis of dimerization of G protein coupled receptors (GPCR) exist. But only in 1999 it became clear by investigation of GABA B receptors that dimerization is the prerequisite for function. Since then our understanding of GPCR function is widened by the fact that nearly all GPCRs form dimers or higher order oligomers. This formation of GPCR homodimers or heterodimers influence the functional properties of a GPCR from that we know of a monomer in its ability to traffic to the cell surface, to bind one or even a variety of ligands, to initiate one or several signalling pathways, to be internalized, or not, and at least to be a therapeutical target. This receptor cross-talk seems to be crucial for fine-tuning of receptor function in controlling physiological processes of a cell. A very large number of GPCRs are known that form heterodimers/oligomers but the functional impact for a lot of these dimers still remains unclear and functional consequences of GPCR heterodimerization are nor predictable. For some GPCR dimers the functional impact is solved, e.g. for GABA B1 and GABA B2 receptors it is known that dimerization is necessary for cell surface expression and function; the taste sensation of sweet or umami is dependent on the formation of taste receptor T1R1, T1R2 and T1R3 complexes and the formation of dopamine 2 receptor/cannabinoid 1 receptor heterodimers result in activation of the Gs instead of Gi when expressed alone.
What do these data contribute to our overall understanding of physiological processes? As long as we have no other hints we have to accept that all possible interactions of GPCRs that are expressed on a given cell type are possible and therefore have to be investigated. to clarify their physiological significance. Especially this counts for the estimation of drug pharmacology targeting a GPCR.
Our group is interested in understanding the physiological processes of hypothalamic weight regulation. Therefore we set out to investigate the interaction of GPCR that are expressed on neurons of the nucleus arcuatus and nucleus paraventricularis. For example we are able to show that the MC3R forms dimers with the ghrelin receptor both are expressed on NPY/AGRP neuron of the nucleus arcuatus. The functional consequences of these dimers have to be investigated.
The determination of GPCR heterodimer function is a great challenge and will provide explanation for so far not understood cellular processes.