Ligand-Dependent\nand G Protein-Dependent Properties\nfor the Sweet Taste Heterodimer, TAS1R2/1R3

The heterodimeric\nsweet taste receptor, TAS1R2/1R3, is\na class\nC G protein-coupled receptor (GPCR) that couples to gustducin (Gt),\na G protein (GP) specifically involved in taste processing. This makes\nTAS1R2/1R3 a possible target for newly developing low caloric ligands\nthat taste sweet to address obesity and diabetes. The activation of\nTAS1R2/1R3 involves the insertion of the GαP C-terminus of the\nGP into the GPCR in response to ligand binding. However, it is not\nknown for sure whether the GP inserts into the TAS1R2 or TAS1R3 intracellular\nregion of this GPCR dimer. Moreover, TAS1R2/1R3 can also connect to\nother GPs, such as Gs, Gi1, Gt3, Go, Gq, and G12. These GPs have different\nC-termini that may modify GPCR signaling. To understand the possible\nGP dependence of sweet perception, we use molecular dynamic (MD) simulations\nto examine the coupling of various GαP C20 termini to TAS1R2/1R3\nfor various steviol glycoside ligands and an artificial sweetener.\nSince the C20 could interact with the transmembrane domain (TMD) of\neither TAS1R2 (TMD2) or TAS1R3 (TMD3), we consider both cases. Without\nany sweetener, we find that the apo GPCR shows similar Go and Gt selectivities,\nwhile all steviol glycoside ligands increase the selectivity of Gt\nbut decrease Go selectivity at TMD2. Interestingly, we find that high\nsweet rebaudioside M (RebM) and RebD ligands show better interactions\nof C20 at TMD3 for the Gt protein, but low sweet RebC and hydRebM\nligands show better interaction of C20 at TMD2 for the Gt protein.\nThus, our MD simulation suggests that TAS1R2/1R3 may couple the GP\nto either 1R2 or to 1R3 and that it can couple other GPs compared\nto Gt. This will likely lead to multimodal functions producing multiple\npatterns of intracellular signaling for sweet taste receptors, depending\non the particular sweetener. Directing the GP to one of the other\nmay have beneficial therapeutic outcomes.