Searchable abstracts of presentations at key conferences in endocrinology

ea0020p330 | Comparative Endocrinology | ECE2009

Comparative analyses between the glycoprotein-hormone receptors and the orphan leucine-rich repeat containing G-protein coupled receptor 4 (LGR4)

Kleinau Gunnar , Gruters Annette , Biebermann Heike , Krause Gerd

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...

ea0020p681 | Signal Transduction | ECE2009

A newly identified loss-of-function mutation in helix 5 reveals new insights into signalling mechanisms of the thyrotropin receptor

Winkler Franziska , Kleinau Gunnar , Gruters Annette , Krude Heiko , Krause Gerd , Biebermann Heike

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 ...

ea0016p653 | Signal transduction | ECE2008

The hinge region of the human TSH-receptor (hTSHR) mediates the activity of a superagonistic human TSH analog and bovine TSH

Mueller Sandra , Kleinau Gunnar , Skudlinski Mariusz , Jaeschke Holger , Krause Gerd , Paschke Ralf

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...

ea0014p609 | (1) | ECE2007

Implications for molecular mechanisms of glycoprotein hormone receptors using a new sequence-structure-function analysis resource

Kleinau Gunnar , Brehm Mara , Wiedemann Urs , Labudde Dirk , Leser Ulf , Krause Gerd

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...

ea0032p577 | Female reproduction | ECE2013

The hinge region of the lutropin receptor mediates different activation mechanisms: CG induces trans- and LH only cis-initialization

Grzesik Paul , Kreuchwig Annika , Teichmann Anke , Furkert Jens , Rutz Claudia , Wiesner Burghard , Kleinau Gunnar , Schulein Ralf , Gromoll Jorg , Krause Gerd

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...

ea0049oc2.3 | Diabetes Prediction and Complications | ECE2017

GLP-1 based multi-agonists-induced signaling includes profound TRP channel involvement in insulin secretion

Khajavi Noushafarin , Finan Brian , Kluth Oliver , Mergler Stefan , Muller Timo , Kleinau Gunnar , Schurmann Annette , Tschop Matthias H , DiMarchi Richard , Krude Heiko , Biebermann Heike

Promiscuous multi-agonists that simultaneously activate two or three key receptors (incretin- and/or glucagon receptor) were recently shown to improve glycemic control in mice. Here we investigated the underlying mechanisms of multi-agonists to enhance insulin secretion in murine islets and human pancreatic β-cells. These mixed agonists display a greater potency in cAMP signaling as compared to the native incretins. However, pharmacological blockade of cAMP signaling only...

ea0041oc12.1 | Obesity | ECE2016

Functional characterization of naturally occurring mutations in the melanocortin receptor accesory protein 2 (MRAP2)

Biebermann Heike , Schonnop Laura , Herrfurth Nikolas , Volckmar Anna-Lena , Muller Anne , Peters Triinu , Herpertz Stephan , Antel Jochen , Hebebrand Johannes , Kleinau Gunnar , Hinney Anke

Introduction: The melanocortin 4 receptor (MC4R) is the most important hypothalamic expressed G protein coupled receptor in weight regulation. Mutations in the MC4R are the most frequent genetic cause of obesity. Recently an accessory protein of the MC4R (melanocortin receptor accessory protein 2, MRAP2) was discovered that was found to play a role in body weight regulation. MRAP2 deficient mice develop early-onset obesity. The mechanisms of disturbed weight regulation is pote...

ea0041ep809 | Obesity | ECE2016

Glucose transporter 1 suppresses melanocortin 4 receptor activity

Muller Anne , Niederstadt Lars , Jyrch Sabine , Jonas Wenke , Meyer Franziska , Grotzinger Carsten , Schurmann Annette , Kleinau Gunnar , Gruters Annette , Krude Heiko , Biebermann Heike

The melanocortin 4 receptor (MC4R) represents the major hypothalamic G-protein coupled receptor (GPCR) controlling feeding behavior and therefore body weight regulation. MC4R is highly expressed in the paraventricular nucleus (PVN) where hormonal and neuroendocrine signals from periphery and arcuate nucleus (ARC) are allocated. MC4R knockout in mice or natural occurring loss-of function variants result in hyperphagia and early-onset obesity. MC4R mutations represent the most f...

ea0022p725 | Signal transduction | ECE2010

Molecular origin of idiopathic central hypogonadism: variable impairment of two signal-transduction pathways due to PROKR2 mutations

Libri Domenico Vladimiro , Bonomi Marco , Busnelli Marta , Kleinau Gunnar , Krausz Csilla , Beck-Peccoz Paolo , Agostino Sinisi Antonio , Persani Luca , ICH study group of the Italian Societies for Endocrinology and Paediatric Endocrinology

ICH is a heterogeneous disease mainly due to functional defects of GnRH neurons. Recent studies have described the importance of prokineticin pathway in the pathogenesis of these defects. In a series of 166 ICH patients we found germline mutations affecting this pathway in about 10% of the cases. PROKR2 gene analysis revealed 3 novel (V158I, T260M, V334M) and 4 already known (L173R, R268C, V274D, V331M) mutations affecting different transmembrane and intracellular regions of t...

ea0016p538 | Obesity | ECE2008

Molecular insights in dysfunctions of the human melanocortin-4-receptor (MC4R) caused by mutations in the third transmembrane domain (TM3) and the second intracellular loop

Tarnow Patrick , Rediger Anne , Widhalm Kurt , Friedel Susann , Kleinau Gunnar , Bolz Hanno , Bettecken Thomas , Hinney Anke , Krause Gerd , Gruters Annette , Biebermann Heike

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...