Evidence for GPCR Dimers

There is overwhelming evidence to support the existence of GPCR dimers: GABAB receptors are obligatory dimers, because they are not exported to the cell surface unless both receptors are present [47-49]. Taste perception provides another instructive example [50]: Of the five different known taste perceptions (sweet, bitter, sour, salty, umami—the typical taste of the amino acids monosodium glutamate and aspartate), three are mediated by G proteincoupled receptors, referred to as T1 receptors for sweet and umami (and further divided into T- R1, T1R2, and T1R3) and T2 receptors for bitter. The perception of sweet is contingent on the presence of T1R2 and T1R3. In contrast, mice rendered genetically deficient in either T1R1 or T1R2 do not respond to the amino acids monosodium glutamate and aspartate. These two examples are formal proof for receptor dimerization, but they do not prove that the receptors work as dimers. It can be argued that oligomer formation is only required for endoplasmic reticulum (ER) export because ER retention motifs are rendered inaccessible in the dimer [51] or because oligomerization favors the assembly of the ER export machinery (as observed with other membrane proteins; see Reference 52). However, using an ingenuous strategy of coex-pressing appropriately ligand-binding and G protein-binding deficient receptors, Hlavackova et al. showed that the dimer also signals [53]. In other words, the data support the hypothetical arrangement of a receptor dimer contacting a single G protein heterotrimer depicted in Fig. 4.2b. This type of arrangement is not only aesthetically pleasing, it also provides for a solution to the foot size/ shoe size problem alluded to in Sections 4.1.2. and 41.3 above [20] and obviates the need to invoke a two-step sequential fit mechanism; one receptor undertakes the docking part to GPy and thus positions Ga to allow for triggering the C-terminal latch by the second receptor.

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