Different functional roles of T1R subunits in the heteromeric taste receptors

TLDR

T1R receptors are class C G protein‑coupled receptors that mediate mammalian sweet and umami tastes, yet their structure–function relationships remain largely unknown. This study demonstrates the distinct functional roles of the extracellular and transmembrane domains of T1R subunits in ligand recognition and G‑protein coupling. By dissecting the Venus flytrap domain of T1R2 and the transmembrane domains of T1R2 and T1R3, the authors showed that T1R2’s VFT domain binds sweeteners, its TM domain mediates G‑protein coupling, and T1R3’s TM domain binds cyclamate and lactisole, and they tested these ligands on the T1R1/T1R3 umami receptor. The results reveal that T1R3’s TM domain is essential for cyclamate recognition and lactisole inhibition, lactisole blocks human T1R1/T1R3 activity and umami taste, cyclamate potentiates glutamate response, and together they demonstrate multiple ligand‑binding sites and distinct roles for T1R2 and T1R3.

Abstract

The T1R receptors, a family of taste-specific class C G proteincoupled receptors, mediate mammalian sweet and umami tastes. The structure–function relationships of T1R receptors remain largely unknown. In this study, we demonstrate the different functional roles of T1R extracellular and transmembrane domains in ligand recognition and G protein coupling. Similar to other family C G protein-coupled receptors, the N-terminal Venus flytrap domain of T1R2 is required for recognizing sweeteners, such as aspartame and neotame. The G protein coupling requires the transmembrane domain of T1R2. Surprisingly, the C-terminal transmembrane domain of T1R3 is required for recognizing sweetener cyclamate and sweet taste inhibitor lactisole. Because T1R3 is the common subunit in the sweet taste receptor and the umami taste receptor, we tested the interaction of lactisole and cyclamate with the umami taste receptor. Lactisole inhibits the activity of the human T1R1/T1R3 receptor, and, as predicted, blocked the umami taste of l -glutamate in human taste tests. Cyclamate does not activate the T1R1/T1R3 receptor by itself, but potentiates the receptor's response to l -glutamate. Taken together, these findings demonstrate the different functional roles of T1R3 and T1R2 and the presence of multiple ligand binding sites on the sweet taste receptor.