Endocrine Abstracts

Thyroid hormones (THs) are transported into their target cells by diverse transmembrane transporter proteins, e.g. by members of the L-type amino acid transporter (LAT) family. The Lat2 is a sodium independent amino acid exchanger and interacts with CD98 for its efficient cell surface expression. So far the role of Lat2 in TH transport including the transport mechanisms is unclear. It is important to determine TH subtype specificity and to identify amino acids at Lat2 which ar...

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...

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 ...

The hinge region of the hTSHR links the extracellular LRR-domain with the transmembrane domain. Recently, we identified mutations E297A, E303A, and D382A in the hinge region with a cell surface expression comparable to the wt but with a strongly reduced bovine TSH (bTSH) binding. The combined triple mutation E297A/E303A/D382A revealed a cell surface expression comparable to the wt but in comparison to the single mutants a more pronounced reduction of bTSH binding (9% of the wt...

Comparison between wild type and mutated glycoprotein hormone receptors (GPHRs) TSHR, FSHR and LHCGR is established to identify determinants involved in molecular activation mechanism. The basic aims of current work are the discrimination of receptor phenotypes according the differences between activity states they represent and hit-assignment of classified phenotypes to 3D-structural positions to reveal functional-structural hotspots and interrelations between determinants th...

G protein-coupled receptors (GPCRs) are critical for signal transduction within neuroendocrine signalling pathways, and genetic mutations in G protein-coupled GPCRs underlie numerous diseases. Inactivating GPCR mutations can impede ligand interactions or signal transduction, or can result in misfolding of nascent receptor proteins and subsequent retention in the endoplasmic reticulum (ER) and thus failure to traffic to the cell surface. Examination of the functionality and cel...

The human luteinizing hormone (LH)/choriogonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands. LHCGR differs to the murine receptor (Lhr) in aminoacid residues potentially involved in qualitative discerning of LH and hCG, the latter absent in rodents. We aim to identify LHCGR residues involved in hCG/LH discrimination, indicating evolutionary determinants of human LH/hCG endocrine system. After comparing the LHCGR and Lhr sequences, we developed eight ...

The lutropin receptor (LHR) is associated with reproduction and becomes activated by choriogonadotropin (CG) or lutropin (LH) resulting in different physiological functions with regard to differing signaling cascades. The underlying mechanisms in receptor/hormone interaction are not yet understood. CG is known to induce trans-activation at LHR oligomers (activates a second receptor), but details of LH mechanisms were not clarified yet.To study this issue...

Mutations in the hypothalamic expressed MC4R gene are the most frequent cause of monogenetic obesity. This Gαs-Protein coupled receptor (GPCR) is activated by endogenous ligands α- and β-MSH and is inhibited by the only known endogenous inverse agonist and antagonist Agouti related peptide (AgRP). Naturally occurring mutations help to understand activation mechanisms of the human MC4R.We previously described a constitutively act...

Study objective: We investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR), on Graves’ Disease and thyroid eye disease. Graves‘ disease (GD), also known as ‘Basedow’s disease‘, is the most common cause for hyperthyroidism, typically presenting in patients between 40-60 years. GD is an autoimmune condition of the thyroid which is caused by autoanti...