TAS2R bitter taste receptors regulate thyroid function.

Dysregulation of thyroid hormones triiodothyronine and thyroxine (T3/T4) can impact metabolism, body composition, and development. Thus, it is critical to identify novel mechanisms that impact T3/T4 production. We found that type 2 taste receptors (TAS2Rs), which are activated by bitter-tasting compounds such as those found in many foods and pharmaceuticals, negatively regulate thyroid-stimulating hormone (TSH)-dependent Ca(2+) increases and TSH-dependent iodide efflux in thyrocytes. Immunohistochemical Tas2r-dependent reporter expression and real-time PCR analyses reveal that human and mouse thyrocytes and the Nthy-Ori 3-1 human thyrocyte line express several TAS2Rs. Five different agonists for thyrocyte-expressed TAS2Rs reduced TSH-dependent Ca(2+) release in Nthy-Ori 3-1 cells, but not basal Ca(2+) levels, in a dose-dependent manner. Ca(2+) responses were unaffected by 6-n-propylthiouracil, consistent with the expression of an unresponsive variant of its cognate receptor, TAS2R38, in these cells. TAS2R agonists also inhibited basal and TSH-dependent iodide efflux. Furthermore, a common TAS2R42 polymorphism is associated with increased serum T4 levels in a human cohort. Our findings indicate that TAS2Rs couple the detection of bitter-tasting compounds to changes in thyrocyte function and T3/T4 production. Thus, TAS2Rs may mediate a protective response to overingestion of toxic materials and could serve as new druggable targets for therapeutic treatment of hypo- or hyperthyroidism.

Extraoral bitter taste receptors as mediators of off-target drug effects.

We present a novel hypothesis that could explain many off-target effects of diverse pharmaceuticals. Specifically, we propose that any drug with a bitter taste could have unintended actions in the body through stimulation of extraoral type 2 taste receptors (T2Rs). T2Rs were first identified in the oral cavity, where they function as bitter taste receptors. However, recent findings indicate that they are also expressed outside the gustatory system, including in the gastrointestinal and respiratory systems. T2R ligands include a diverse array of natural and synthetic compounds, many of which are toxins. Notably, many pharmaceuticals taste bitter, with compounds such as chloroquine, haloperidol, erythromycin, procainamide, and ofloxacin known to activate T2Rs. Bitter-tasting compounds can have specific physiological effects in T2R-expressing cells. For example, T2Rs are found in some gastrointestinal endocrine cells, including those that secrete the peptide hormones (e.g., ghrelin and glucagon-like peptide-1) in response to stimulation by bitter-tasting compounds. In the respiratory system, stimulation of T2Rs expressed in respiratory epithelia and smooth muscle has been implicated in protective airway reflexes, ciliary beating, and bronchodilation. If our hypothesis is confirmed, it would offer a new paradigm for understanding the off-target actions of diverse drugs and could reveal potential new therapeutic targets.

Odorants specifically modulate chemotaxis and tissue retention of CD4+ T cells via cyclic adenosine monophosphate induction.

Retention of T cells within affected tissue is a critical component of adaptive immune inflammation. However, the mechanisms involved in T cell retention remain largely undefined. Previous studies revealed the capacity of cAMP signaling to regulate immune cell migration, as well as dynamic regulation of receptors that could induce cAMP production in immune cells. The potential for cAMP to act as a retention signal has been mostly unexplored, partially as a result of this second messenger's well-characterized inhibition of effector function in immune cells. Here, we report that cAMP regulates the tissue retention of mouse T cells at concentrations well below those that inhibited proliferation or decreased acquisition of an effector phenotype. Stimulation of CD4+ T cells with odorants known to be cognate ligands for T cell-expressed olfactory receptors induced cAMP and inhibited chemokine-driven chemotaxis without decreasing T cell proliferation or effector functions. Similar effects were observed following treatment with relatively low concentrations of the cAMP analog Sp-5,6-dichloro-1-ß-d-ribofuranosylbenzimidazole-3',5'-monophosphorothioate. Furthermore, pretreatment with odorants or cAMP at concentrations that did not inhibit effector function induced T cell tissue retention in mice by inhibiting chemokine-dependent T cell egress from the footpad to the draining lymph node. Together, these results suggest that odorant receptor-mediated increases in intracellular cAMP can modulate T cell tissue trafficking and may offer new therapeutic targets for controlling T cell tissue accumulation.