Beyond taste: extraoral TAS1R3 signaling in nutrient sensing and osteoclastogenesis

The taste receptor type 1 (TAS1R) family includes class C G protein-coupled receptors that mediate sweet and umami taste perception through well-defined receptor complexes and downstream signaling pathways. Recently, TAS1Rs have been shown to be expressed not only in the oral cavity, but also in a wide variety of extraoral tissues, raising the possibility that they function as systemic nutrient sensors. However, the receptor composition and the molecular mechanisms by which extraoral TAS1Rs function remain unclear.

In the oral cavity, TAS1Rs function as heterodimeric complexes; TAS1R2/TAS1R3 mediates sweet taste perception, whereas TAS1R1/TAS1R3 mediates umami taste perception. These receptors primarily activate the canonical PLCβ2-Ca²⁺ signaling pathway to transduce taste signals. In contrast, accumulating evidence indicates that, in osteoclasts, TAS1R3 is largely expressed independently of other TAS1R family members and functions predominantly as a homodimer. In this context, TAS1R3 acts as a glucose-sensing receptor and enhances p38 MAPK activation, thereby promoting osteoclast differentiation. These findings highlight the fundamental differences between oral and osteoclastic TAS1R signaling in terms of receptor configuration, ligand recognition, and downstream signaling pathways.

Collectively, these observations suggest that extraoral taste receptors play previously unknown roles in bone metabolism. TAS1R3, which is expressed in osteoclasts, may act as a nutrient sensor connecting the metabolic status to osteoclast differentiation and function. Elucidating the unique receptor properties and signaling mechanisms of TAS1R3 in bone tissue will provide new insights into bone metabolic regulation and highlight the therapeutic potential of targeting TAS1R3 in metabolic bone diseases.