The Hidden One: What We Know About Bitter Taste Receptor 39

Abstract

Over thousands of years of evolution, animals have developed many ways to protect themselves. One of the most protective ways to avoid disease is to prevent the absorption of harmful components. This protective function is a basic role of bitter taste receptors (TAS2Rs), a G protein-coupled receptor family, whose presence in extraoral tissues has intrigued many researchers. In humans, there are 25 TAS2Rs, and although we know a great deal about some of them, others are still shrouded in mystery. One in this latter category is bitter taste receptor 39 (TAS2R39). Besides the oral cavity, it has also been found in the gastrointestinal tract and the respiratory, nervous and reproductive systems. TAS2R39 is a relatively non-selective receptor, which means that it can be activated by a range of mostly plant-derived compounds such as theaflavins, catechins and isoflavones. On the other hand, few antagonists for this receptor are available, since only some flavones have antagonistic properties (all of them detailed in the document). The primary role of TAS2R39 is to sense the bitter components of food and protect the organism from harmful compounds. There is also some indication that this bitter taste receptor regulates enterohormones and in turn, regulates food intake. In the respiratory system, it may be involved in the congestion process of allergic rhinitis and may stimulate inflammatory cytokines. However, more thorough research is needed to determine the precise role of TAS2R39 in these and other tissues.

Keywords: GPCR; TAS2R39; TAS2R39 agonist; TAS2R39 antagonist; bitter taste; catechin; food intake; respiratory system.

Figure 1

The Bitter Taste Receptor Signaling Pathway: when the ligand binds to the TAS2R, a conformational change is induced. This in turn triggers the dissociation of the α-subunit of gustducin from the β- and γ-subunits. This dissociation of subunits signifies two divergent pathways of signal transduction. In the first of these, β- and γ-subunits activate the β2 isoform of phospholipase C (PLCβ2), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP₂) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). IP₃ then travels to Endoplasmic Reticulum (ER), where it binds to its receptor (IP₃R), leading to the secretion of Ca₂ ⁺ from the ER into the cytoplasm. This increase in intracellular Ca₂ ⁺ levels leads to the activation of sodium-selective transmembrane transporters TRPM4 and 5, thereby depolarizing the cellular membrane. Depolarization activates voltage-gated sodium channels (VGNC), thus hastening depolarization. When the action potential (AP) is reached, the calcium homeostasis modulator 1 and 3 (CALHM1/3) channel and pannexin 1 channels are activated, which leads to the transportation of ATP from cytoplasm to the intercellular space. Through P2X ionotropic purinergic receptors 2 and 3 (P2X2/P2X3), ATP is taken into the afferent nerve, thereby propagating the signal further down. The other pathway occurs through the α-subunit of gustducin, but the exact mechanism of signal propagation is unknown. It is postulated that α-gustducin lowers the level of cAMP by activating its hydrolysation though phosphodiesterase (PDE), but the next steps are still unknown. The lowering of cAMP may lead to a decrease in the levels of cNMPs intracellularly, which may regulate protein kinases and in turn regulate the ion activity in the cell. It is also possible that cNMP directly regulates cNMP-gated ion channels, thereby depolarizing the membrane and eliciting the release of the neurotransmitter.