Adenosine A2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A2A receptor tightly interacts structurally and functionally with the dopamine D2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A2A and D2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A2A/D2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A1 receptors. Therefore, A2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D2 receptors, group I metabotropic mGlu5 glutamate receptors and cannabinoid CB1 receptors, and by triggering the cAMP-protein kinase A signaling cascade. 相似文献
Hemodynamic forces applied at the apical surface of vascular endothelial cells may be redistributed to and amplified at remote
intracellular organelles and protein complexes where they are transduced to biochemical signals. In this study we sought to
quantify the effects of cellular material inhomogeneities and discrete attachment points on intracellular stresses resulting
from physiological fluid flow. Steady-state shear- and magnetic bead-induced stress, strain, and displacement distributions
were determined from finite-element stress analysis of a cell-specific, multicomponent elastic continuum model developed from
multimodal fluorescence images of confluent endothelial cell (EC) monolayers and their nuclei. Focal adhesion locations and
areas were determined from quantitative total internal reflection fluorescence microscopy and verified using green fluorescence
protein–focal adhesion kinase (GFP–FAK). The model predicts that shear stress induces small heterogeneous deformations of
the endothelial cell cytoplasm on the order of <100 nm. However, strain and stress were amplified 10–100-fold over apical
values in and around the high-modulus nucleus and near focal adhesions (FAs) and stress distributions depended on flow direction.
The presence of a 0.4 μm glycocalyx was predicted to increase intracellular stresses by ∼2-fold. The model of magnetic bead
twisting rheometry also predicted heterogeneous stress, strain, and displacement fields resulting from material heterogeneities
and FAs. Thus, large differences in moduli between the nucleus and cytoplasm and the juxtaposition of constrained regions
(e.g. FAs) and unattached regions provide two mechanisms of stress amplification in sheared endothelial cells. Such phenomena
may play a role in subcellular localization of early mechanotransduction events. 相似文献
Increases in several ceramide species have been shown by non-targeted lipid profiling (lipidomics) of the rat hippocampus
after kainate lesions (Guan et al. FASEB J 20:1152–1161, 2006). This study was carried out to examine possible effects of ceramide species on exocytosis. Significant increase in membrane
capacitance in voltage-clamped rat pheochromocytoma (PC12) cells, an indication of exocytosis, was detected immediately after
external application of C2, C6, and C18 ceramide. In contrast, no increase in capacitance was found after addition of C16
and C20 ceramide, or DMSO vehicle. The effect of ceramide on exocytosis was dependent on the integrity of lipid rafts. Treatment
of cells with the cholesterol binding agent/disruptor of lipid rafts, methyl β cyclodextrin, prior to addition of C18 ceramide
suppressed the increase in capacitance induced by this lipid species. The ability of C2, C6 and C18 ceramide to trigger exocytosis
was confirmed using total internal reflection fluorescence microscopy (TIRFM) experiments. External application of these species
caused an exponential decrease in the number of subplasmalemmal neuropeptide Y (NPY)-enhanced green fluorescence protein (EGFP)
labeled vesicles, indicating exocytosis. Interestingly, C18 is also the ceramide species that showed the greatest increase
in the rat hippocampus after kainate excitotoxicity. It is postulated that C18 ceramide might facilitate exocytosis of glutamate
from damaged neurons, thus propagating neuronal injury. 相似文献
Aims: To investigate the value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in a cohort of a community’s residents who were diagnosed as pre-diabetes, and to evaluate the association of VAT and SAT with insulin resistance.Methods: This study was based on cross-sectional analysis of data from 107 adults. VAT and SAT were assessed by computed tomography. Insulin resistance was defined by homeostasis model assessment of insulin resistance >2.69. The relationship of VAT and SAT with insulin resistance were examined by linear regression. Logistic regression was used to analyze the association of VAT and SAT with insulin resistance.Results: A total of 87 subjects had VAT ≥100?cm2. Thirty-six out of 107 (33.6%) subjects were detected to have insulin resistance, 71 were normal (66.4%), and all had insulin resistance with VAT ≥100?cm2. VAT (r?=?0.378, p?.001) and SAT (r?=?0.357, p?.001) were significantly and positively correlated with insulin resistance. In multiple regression analysis when VAT and SAT were simultaneously included after adjustment for age, gender, BMI, and WC, the association between VAT and insulin resistance was still maintained (p?=?.003), but that of SAT was lost.Conclusion: Pre-diabetic subjects with insulin resistance had elevated levels of VAT. VAT was more strongly associated with insulin resistance than SAT in Chinese subjects with pre-diabetes. 相似文献
Simple and facile methods for the synthesis of deuterium‐labeled obeticholic acid and its 2 metabolites, glycine and taurine conjugates of obeticholic acid, are described herein. The 3 deuterated compounds were applicable for use as internal standards in drug development. 相似文献