Unraveling the Molecular Basis for Successful Thyroid Hormone Replacement Therapy: The Need for New Thyroid Tissue- and Pathway-Specific Biomarkers.

Thyroid function is conventionally assessed by measurement of thyroid-stimulating hormone (TSH) and free circulating thyroid hormones, which is in most cases sufficient for correct diagnosis and monitoring of treatment efficiency. However, several conditions exist, in which these parameters may be insufficient or even misleading. For instance, both, a TSH-secreting pituitary adenoma and a mutation of thyroid hormone receptor ß present with high levels of TSH and circulating hormones, but the optimal treatment is substantially different. Likewise, changes in thyroid hormone receptor α signaling are not captured by routine assessment of thyroid status, as serum parameters are usually inconspicuous. Therefore, new biomarkers are urgently needed to improve the diagnostic management and monitor treatment efficiency for e. g., replacement therapy in hypothyroidism or thyroid hormone resistance. By comparing animal models to human data, the present minireview summarizes the status of this search for new tissue- and pathway-specific biomarkers of thyroid hormone action.

The Trace Amine-Associated Receptor 1 Agonist 3-Iodothyronamine Induces Biased Signaling at the Serotonin 1b Receptor.

Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the Gs/adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid hormone derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyrexic effects, which might be centrally mediated in the hypothalamus in rodents. However, the observed anapyrexic effect of 3-T1AM persists in Taar1 knock-out mice which raises the question whether further GPCRs are potential targets for 3-T1AM and mediate the observed physiological effect. Anapyrexia has been observed to be related to action on aminergic receptors such as the serotonin receptor 1b (5-HT1b). This receptor primarily activates the Gi/o mediated pathway and PLC signaling through the Gßγ of Gi/o. Since the expression profiles of TAAR1 and 5-HT1b overlap, we questioned whether 3-T1AM may activate 5-HT1b. Finally, we also evaluated heteromerization between these two GPCRs and tested signaling under co-expressed conditions. In this study, we showed, that 3-T1AM can induce Gi/o signaling through 5-HT1b in a concentration of 10 µM. Strikingly, at 5-HT1b the ligand 3-T1AM only activates the Gi/o mediated reduction of cAMP accumulation, but not PLC activation. Co-stimulation of 5-HT1b by both ligands did not lead to additive or synergistic signaling effects. In addition, we confirmed the capacity for heteromerization between TAAR1 and 5-HT1b. Under co-expression of TAAR1 and HTR1b, 3-T1AM action is only mediated via TAAR1 and activation of 5-HT1b is abrogated. In conclusion, we found evidence for 5-HT1b as a new receptor target for 3-T1AM, albeit with a different signaling effect than the endogenous ligand. Altogether, this indicates a complex interrelation of signaling effects between the investigated GPCRs and respective ligands.

Neuroblast differentiation during development and in neuroblastoma requires KIF1Bß-mediated transport of TRKA.

We recently identified pathogenic KIF1Bß mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bß in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bß is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bß mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bß-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bß. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bß independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bß loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bß mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.