Illuminating the Activation Mechanisms and Allosteric Properties of Metabotropic Glutamate Receptors.

Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors.

Proc Natl Acad Sci U S A. 2013 Mar 4;
Doumazane E, Scholler P, Fabre L, Zwier JM, Trinquet E, Pin JP, Rondard P

In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation of the effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors. HubMed – drug


HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.

Proc Natl Acad Sci U S A. 2013 Mar 4;
Xiong Y, Zhao K, Wu J, Xu Z, Jin S, Zhang YQ

Neurons from the brains of Alzheimer’s disease (AD) and related tauopathy patients contain neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs); however, tau hyperphosphorylation leads to loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, MT-stabilizing drugs such as paclitaxel and epothilone D have been shown as possible therapies for AD and related tauopathies. However, MT-stabilizing drugs have common side effects such as neuropathy and neutropenia. To find previously undescribed suppressors of tau-induced MT defects, we established a Drosophila model ectopically expressing human tau in muscle cells, which allow for clear visualization of the MT network. Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation, consistent with previous reports in AD patients and mouse models. From a genetic screen, we found that a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. These findings reveal HDAC6 as a unique potential drug target for AD and related tauopathies. HubMed – drug


Development and validation of an HPLC method to determine the stability of fentanyl citrate and bupivacaine hydrochloride mixtures in infusion solutions.

Eur J Hosp Pharm Sci Pract. 2012 Oct; 19(5): 447-451
Piekarski M, Jelin’ska A, Szymczak K

The use of a combination of different drugs in postoperative analgesia extends the time of analgesia, makes it more efficient and allows the use of lower drug doses, which leads to less risk of side effects and drug dependence. The aim of this study was to develop and validate an HPLC method to determine the stability of fentanyl citrate and bupivacaine hydrochloride mixtures in standard infusion solutions of 0.9% sodium chloride and 5% glucose.AFTER OPTIMISATION, THE HPLC METHOD PARAMETERS WERE AS FOLLOWS: LiChrospher 100 CN, 250×4 mm (10 µm) column; mobile phase: mixture of acetonitrile and phosphate buffer at pH 2.8 (3:7, V/V) with addition of 0.08 g/l potassium chloride; flow rate: 1.5 ml/min; column temperature: 30°C; spectrophotometric detection at 210 nm. Development of the method involved checking the impact of acetonitrile and KCl concentrations in the mobile phase and choosing the internal standard. Method validation included determining the specificity of the method, its accuracy, linearity, precision, repeatability, limits of detection and quantification.The retention times of bupivacaine hydrochloride, fentanyl citrate and procaine hydrochloride, used as an internal standard, were approximately 10 min, 15 min and 5 min, respectively. Method validation confirmed its selectivity, accuracy and precision. The average values of the variation and accuracy coefficients were 0.70% and 99.02% for bupivacaine hydrochloride, and 1.76% and 104.53% for fentanyl citrate. The intermediate precision values were 1.25% for bupivacaine hydrochloride and 1.52% for fentanyl citrate. HubMed – drug


Social motives for drinking in students should not be neglected in efforts to decrease problematic drinking.

Health Educ Res. 2013 Mar 13;
Van Damme J, Maes L, Clays E, Rosiers JF, Van Hal G, Hublet A

High heavy drinking prevalence persists in students. Recently, drinking motivation received a lot of attention as an important determinant. Enhancement and coping motives are mostly positively related and conformity motives are mostly negatively related with heavy drinking. Relations are less clear for social motives. This study aimed at gaining more insight in the role of drinking motives in heavy drinking students. Overall, 15 897 Belgian university and college students (mean age: 20.7, SD = 2.6) anonymously participated in an online survey. Logistic regressions tested relationships between motives and problematic drinking (>weekly drinking, ?monthly binge drinking and being at risk for problematic drinking by the Alcohol Use Disorders Identification Test [AUDIT]). Social motives had the highest prevalence, followed by enhancement, coping and conformity motives. Men engaged more in problematic drinking and reported more motives, except for coping. Enhancement, coping and social-motivated students have higher chances for problematic drinking, while the opposite is true for conformity-motivated students. Although this study found a similar ranking of motives as in other studies, a relationship between problematic drinking and all motives, including social motives, was revealed. This might indicate the different functions of social motives in heavy drinking in different cultures/sub-populations and countries. This finding is relevant for the development of interventions. HubMed – drug



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