Ligand-Dependent and G Protein-Dependent Properties for the Sweet Taste Heterodimer, TAS1R2/1R3

The heterodimeric sweet taste receptor, TAS1R2/1R3, is a class C G protein-coupled receptor (GPCR) that couples to gustducin (Gt), a G protein (GP) specifically involved in taste processing. This makes TAS1R2/1R3 a possible target for newly developing low caloric ligands that taste sweet to address obesity and diabetes. The activation of TAS1R2/1R3 involves the insertion of the G alpha P C-terminus of the GP into the GPCR in response to ligand binding. However, it is not known for sure whether the GP inserts into the TAS1R2 or TAS1R3 intracellular region of this GPCR dimer. Moreover, TAS1R2/1R3 can also connect to other GPs, such as Gs, Gi1, Gt3, Go, Gq, and G12. These GPs have different C-termini that may modify GPCR signaling. To understand the possible GP dependence of sweet perception, we use molecular dynamic (MD) simulations to examine the coupling of various G alpha P C20 termini to TAS1R2/1R3 for various steviol glycoside ligands and an artificial sweetener. Since the C20 could interact with the transmembrane domain (TMD) of either TAS1R2 (TMD2) or TAS1R3 (TMD3), we consider both cases. Without any sweetener, we find that the apo GPCR shows similar Go and Gt selectivities, while all steviol glycoside ligands increase the selectivity of Gt but decrease Go selectivity at TMD2. Interestingly, we find that high sweet rebaudioside M (RebM) and RebD ligands show better interactions of C20 at TMD3 for the Gt protein, but low sweet RebC and hydRebM ligands show better interaction of C20 at TMD2 for the Gt protein. Thus, our MD simulation suggests that TAS1R2/1R3 may couple the GP to either 1R2 or to 1R3 and that it can couple other GPs compared to Gt. This will likely lead to multimodal functions producing multiple patterns of intracellular signaling for sweet taste receptors, depending on the particular sweetener. Directing the GP to one of the other may have beneficial therapeutic outcomes.