An update on extra-oral bitter taste receptors

Abstract

Bitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.

Keywords: Bitter compounds; Bitter taste-sensing type 2 receptors (TAS2Rs); Cancer; Extraoral tissues; G-protein coupled receptors (GPCRs); Innate immunity; Muscle contractility; TAS2R polymorphisms.

Fig. 1

Xanthohumol (XN), a prenylated flavonoid isolated from Hops (Humulus lupulus L.) is an agonist of TAS2R1, 14, and 40. Simultaneously, it acts as a potent anticancer agent for multiple types of cancer. However, so far there are no evidence supporting a linkage between TAS2Rs and XN-mediated anti-tumor activity

Fig. 2

Overview of the canonical TAS2R signalling pathway. Upon TAS2R activation, the G-protein gustducin dissociates and activates phopholipase Cβ2 (PLCβ2), which subsequently leads to elevation in Ca²⁺ from inositol-1,4,5-triphosphate (IP3)-sensitive Ca²⁺ stores. This in turn activates transient receptor potential cation channel subfamily M member 5 (TRPM5), alters membrane potential (depolarisation), and triggers the release of the neurotransmitter, adenosine-5'-triphosphate (ATP), via the calcium homeostasis modulator 1 CALHM1 or CALHM1/CALHM3 ion channel. All these events together contribute to a wide range of cellular response

Fig. 3

Model showing TAS2R-dependent modulation of progesterone (P4)’s role in protecting from pregnancy. P4 binds to TAS2Rs found in extravillous trophoblast (EVT) cells and enhances the release of progesterone-induced blocking factor (PIBF), perhaps via the canonical signalling cascade. This, subsequently binds to the PIBF receptor, which heterodimerises with the IL-4 receptor to activate the signal transducer and activator of transcription 6 (STAT6) transcription pathway for cytokine production by the type 2 T helper cells (Th2). On the type 1 T helper cells (Th1), PIBF acts to inhibit the STAT4 pathway by promoting interaction of suppressor of cytokine signalling 3 (SOCS-3) with the IL-12R receptor to attenuate Th1 cytokine production. Furthermore, PIBF inhibits the cytological activity (natural killer) of NK cells by blocking perforin and lytic enzyme degranulation. Finally, PIBF interacts with B cells, increasing the production of asymmetric antibodies. All this reduces cellular cytotoxicity and controls immunosuppression