Future Directions And New Concepts

The inclusion of G protein-independent pathways in future ligand screening procedures will certainly help to deorphanize further orphan 7TM proteins. However, additional strategies may be necessary to deorphanize all remaining orphans. Accumulating evidence indicates that transfection of a single receptor cDNA into fibroblastic cell lines (typically CHO cells) may not always be sufficient for functional expression. The majority of GPCRs exist as dimers (or higher oligomers). This includes self-association into homodimers and association between different GPCRs into heterodimers. Heterodimer formation has been most extensively studied for non-orphan GPCRs demonstrating the reciprocal influence of heterodimerization on the functional properties of both protomers. Interestingly, several of the known heterodimers include also orphan 7TM proteins (Fig. 7.3) [73] . The first and most extensively studied heterodimer that is composed of an orphan and a non-orphan GPCR is the obligatory metabotropic y-aminobutyric acid B (GABAb) receptor heterodi-mer. A functional GABAB receptor is composed of two homologous subunits called GABAbi and GABAb2 [74-76]. Whereas GABAbi provides ligand binding, the orphan GABAB2 7TM protein promotes efficient trafficking of GABAB1 to the cell surface and G protein coupling [77] . An intracellular endoplasmic reticulum retention signal on GABAB1, which prevents GABAB1 from reaching the cell surface by itself, is masked in the GABAB1/GABAB2 heterodimer.

A similar configuration has been reported for the T1R taste receptors. T1R1 and T1R2, originally discovered as orphans, have subsequently been deorpha-nized by the discovery of T1R3 , their obligatory heterodimerization partner. Whereas T1R./T1R3 heterodimers respond rather to sweet stimuli such as aspartame, the T1R1/T1R3 heterodimer responds to the umami taste of L-glutamate [78, 79]. Within these heterodimers, T1R1 and T1R2 bind their respective ligands with their large extracellular domain, whereas T1R3 is devoid of any ligand binding capacity [78-80].

Orphan 7TM

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