Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression

Abstract

Trace amine-associated receptor 1 (Taar1) has been suggested as putative receptor of thyronamines. These are aminergic messengers with potential metabolic and neurological effects countering their contingent precursors, the thyroid hormones (THs). Recently, we found Taar1 to be localized at the primary cilia of rodent thyroid epithelial cells in vitro and in situ. Thus, Taar1 is present in a location of thyroid follicles where it might be involved in regulation of cathepsin-mediated proteolytic processing of thyroglobulin, and consequently TH synthesis. In this study, taar1 knock-out male mice (taar1-/-) were used to determine whether Taar1 function would entail differential alterations in thyroid states of young and adult animals. Analyses of blood serum revealed unaltered T4 and T3 concentrations and unaltered T3-over-T4 ratios upon Taar1 deficiency accompanied, however, by elevated TSH concentrations. Interestingly, TSH receptors, typically localized at the basolateral plasma membrane domain of wild type controls, were located at vesicular membranes in thyrocytes of taar1-/- mice. In addition, determination of epithelial extensions in taar1-/- thyroids showed prismatic cells, which might indicate activation states higher than in the wild type. While gross degradation of thyroglobulin was comparable to controls, deregulated thyroglobulin turnover in taar1-/- mice was indicated by luminal accumulation of covalently cross-linked thyroglobulin storage forms. These findings were in line with decreased proteolytic activities of thyroglobulin-solubilizing and -processing proteases, due to upregulated cystatins acting as their endogenous inhibitors in situ. In conclusion, Taar1-deficient mice are hyperthyrotropinemic in the absence of respective signs of primary hypothyroidism such as changes in body weight or TH concentrations in blood serum. Thyrocytes of taar1-/- mice are characterized by non-canonical TSH receptor localization in intracellular compartments, which is accompanied by altered thyroglobulin turnover due to a disbalanced proteolytic network. These finding are of significance considering the rising popularity of using TAAR1 agonists or antagonists as neuromodulating pharmacological drugs. Our study highlights the importance of further evaluating potential off-target effects regarding TSH receptor mislocalization and the thyroglobulin processing machinery, which may not only affect the TH-generating thyroid gland, but may emanate to other TH target organs like the CNS dependent on their proper supply.

The role of functional thyroid capacity in pituitary thyroid feedback regulation

“…Measuring TSH immunological activity may have slightly overestimated its biological effect at higher concentrations because TRH simulation may produce biologically less active variants of the hormone. 42 Importantly, the classical T3-dependent genomic pathways are complemented by post-transcriptional nongenomic T3 effects. 40,41 The classical concept of negative hypothalamic-pituitary feedback regulation by thyroid hormones has recently been improved to describe more appropriately the diverse facets of pituitary control.…”

“…40 TSH receptor transpositioning was recently discovered as a new thyronamine-Taar1-related signalling pathway in the mouse, whose disruption reduced TSH sensitivity (TSH receptor resistance). 42 Importantly, the classical T3-dependent genomic pathways are complemented by post-transcriptional nongenomic T3 effects. 43 These tend to precede the specific genomic actions and rapidly control basal cellular activity levels.…”

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression

“…For a first validation of this antibody, we tested its specificity in cell lines and murine brain tissue by comparing it with another well-characterized anti-MCT8 antibody (HPA003353, Lot no. A61491; Atlas) (22,23,44,45) that is no longer available.…”

Integrated miRNA and mRNA expression profiling identifies novel targets and pathological mechanisms in autoimmune thyroid diseases

“…The relationship between these structures and the Golgi apparatus suggests that cilium may act as sensory regulators in the thyroid to modulate hormone secretion [14]. Indeed, trace amine-associated receptor 1 (Taar1), a G-protein-coupled receptor, have been described to be present in primary cilium of thyroid rodent cells and has been attributed to function in thyroid hormones liberation, thyroid autoregulation and homeostatic thyroid stimulating hormone receptor maintenance [23,24]. Alterations of primary cilia have also been associated in the regulation of cancer development towards the control of metabolic phenotypes [25,26].…”