Endocrine Abstracts

For over two decades the hypothesis of dimerization of G protein coupled receptors (GPCR) exist. But only in 1999 it became clear by investigation of GABA B receptors that dimerization is the prerequisite for function. Since then our understanding of GPCR function is widened by the fact that nearly all GPCRs form dimers or higher order oligomers. This formation of GPCR homodimers or heterodimers influence the functional properties of a GPCR from that we know of a monomer in it...

The endogenous decarboxylated thyroid hormone (TH) metabolite 3-Iodothyronamine (3-T1AM) exerts partially TH antagonistic effects in rodents and was shown to suppress the hypothalamic pituitary thyroid axis in rats after single dose application. Therefore, it might play a role in maintaining TH homoeostasis. Among the molecular targets of 3-T1AM are G protein-coupled receptors like the trace amine associated receptor 1 (TAAR1) and adrenergic receptors. Furthermore, 3-T1AM was ...

In recent decades intensive studies on the glycoprotein-hormone receptors (GPHRs) and their respective hormones have provided a number of molecular insights into the relationship between the structure and function of these proteins. This knowledge includes an understanding of hormone binding, of naturally occurring mutations nad mechanisms of signal transduction and G-protein binding processes.Together with the relaxin family peptide receptors (RxFP) the...

The melanocortin 4 receptor (MC4R) plays a prominent role in hypothalamic weight regulation. Activation of this receptor results by so far not understood mechanisms in a decrease of food-intake and an increase of energy expenditure. Recently a functional role downstream of MC4R signalling for brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B receptor (TrkB) was reported. TrkB signalling influences several neuronal processes like synapse for...

The melanocortin 4 receptor (MC4R), a G protein coupled receptor, has a prominent role in hypothalamic weight regulation. The MC4R was recently shown to form receptor dimers. The cannabinoid 1 receptor (CB1R) is the nearest phylogenetic relative of MC4R but fails to interact with the MC4R in vitro. In this study we aim to investigate receptor domains that are necessary for MC4R interaction. Four different chimeric receptors of MC4R and CB1R were constructed. The generated cons...

By a systematic approach we investigated the interaction of a selective number of GPCRs that are expressed in the arcuate nucleus and known to play an essential role in hypothalamic weight regulation. Based on the results of a sandwich ELISA and fluorescence resonance energy transfer (FRET) approach we report the interaction of the melanocortin three receptor (MC3R) and the growth hormone secretagogue receptor (GHSR) which are coexpressed on arcuate NPY/AgRP neurons. Fu...

In two siblings suffering from congenital hypothyroidism we identified a homozygous missence mutation Ala579Val in transmembrane helix 5 of the thyrotropin receptor (TSHR) gene which motivated us to investigate molecular details of this mutation.We were interested, firstly, in the functional effects regarding signal transduction and, secondly, in the particular structural properties of the wild type receptor and the Ala579Val mutant. The aim was to gain ...

Background: Defective thyroid gland development occurs in 80% of congenital hypothyroidism (incidence of 1:3000–1:4000). Only <5% have been shown to be caused by molecular genetic defects in few transcription factor genes (Nkx2.1, Nkx2.5, Foxe1, Pax8, Hhex) which are known to play a role in thyroid gland development. Therefore, other genes with a critical role in early thyroid development are likely to be involved in the pathogenesis of thyroid dysgenesis.<p class...

Objective: The NKX2-1 gene, also known as TITF-1, TTF-1 or T/ebp, is a member of the homeodomain-containing NK-2 transcription factor gene family and expressed in early development of thyroid, lung and forebrain. Initial screening of patients with isolated congenital hypothyroidism failed to show mutations. The first human heterozygous deletion affecting the NKX2-1 gene to be reported was a neonate with respiratory failure, primary hypothyroidism and neurological signs matchin...

Food intake is centrally regulated in hypothalamic nuclei. Peripheral hormonal signals activate their corresponding receptors in the arcuate nucleus (arc) and modulate the expression of pro-opiomelanocortin (POMC) and neuropetide Y (NPY)/agouti-related-protein (AgRP). Cleavage products of POMC stimulate melanocortin-4-receptors (MC4R) in the paraventricular nucleus (PVN) to inhibit food intake or stimulate MC3Rs in the arc to activate a feedback loop. Further mor...