Differential Modulation of Beta-Adrenergic Receptor Signaling by Trace Amine-Associated Receptor 1 Agonists

Trace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR), phenylethylamine (PEA), octopamine (OA), but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR) octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes

A Piece of the Puzzle: The Bone Health Index of the BoneXpert Software Reflects Cortical Bone Mineral Density in Pediatric and Adolescent Patients.

INTRODUCTION:Suspected osteopathology in chronically ill children often necessitates the assessment of bone mineral density. The most frequently used methods are dual-energy X-ray-absorption (DXA) and peripheral quantitative computed tomography (pQCT). The BoneXpert software provides an automated radiogrammatic method to assess skeletal age from digitalized X-rays of the left hand. Furthermore, the program calculates the Bone Health Index (BHI), a measure of cortical thickness and mineralization, which is obtained from indices of three metacarpal bones. In our study, we analyzed the manner in which BHI information provided by BoneXpert compares with DXA or pQCT measurements in youths. STUDY DESIGN:The BHI was retrospectively obtained using digitalized X-rays of the left hand and compared with the results of 203 corresponding DXA readings (Lunar Prodigy, GE Healthcare) of the lumbar vertebrae and femur as well as 117 pQCT readings (XCT 900, Stratec) of the distal radius. RESULTS:The BHI values showed a strong positive correlation with the DXA readings at each and all lumbar vertebrae (L1 -L4: r = 0.73; P < 0.0001). The age-adjusted Z-score of L1 -L4 and the height-adjusted score showed a positive correlation with the BHI-SDS (standard deviation score, r = 0.23; P < 0.002 and r = 0.27; P < 0.001, respectively). Total bone mineral density, as assessed via pQCT, also positively correlated with the BHI (r = 0.39; P < 0.0001), but the trabecular values displayed only a weak correlation. CONCLUSIONS:The BHI obtained using BoneXpert can be a useful parameter in the assessment of bone health in children in most cases. This technique provides observer-independent information on cortical thickness and mineralization based on X-ray imaging of the hands

Positive association of BMD values obtained via BoneXpert and pQCT (XCT 900 Stratec®).

<p>A) BHI readings obtained using BoneXpert showed a positive correlation with BMD readings at the distal radius as measured via pQCT (XCT 900 Stratec®; r = 0.39; P < 0.0001). B) Accordingly, the SDS of the pQCT method (QCTOT SDS total, vertical axis) and the BoneXpert (BHI SDS, horizontal axis) were positively correlated (r = 0.3; P = 0.003). The predicted values based on bivariate regression analysis are indicated as a solid line. The dashed lines represent the 95% confidence interval.</p

Results of the DXA measurements.

<p>Results of the DXA measurements.</p

Results of the pQCT readings.

<p>Results of the pQCT readings.</p

Positive association of BMD values obtained via BoneXpert and DXA scan.

<p>A) BMD readings of the lumbar spine (L1-L4) obtained by Lunar Prodigy (GE Healthcare) as a function of BHI obtained by BoneXpert (r = 0.73; P < 0.0001). B) Age-adjusted DXA Z-scores as a function of BHI SDS obtained via BoneXpert (r = 0.23; P = 0.02). C) DXA-Z scores, adjusted for patient height (HAZ) as a function of BHI SDS using BoneXpert (r = 0.27; P < 0.0001). For all figures, the predicted values based on bivariate regression analysis are indicated as solid line. The dashed lines represent the 95% confidence interval.</p

Descriptive statistics of relevant patient clinical data.

<p>Descriptive statistics of relevant patient clinical data.</p