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101.
《Journal of receptor and signal transduction research》2013,33(1):24-30
In this study we examined whether the levels of gene expressions of the three β- adrenergic receptor (βAR) subtypes, β1, β2, and β3, contribute to age-related increase in βAR density. Liver membranes and total RNA were prepared from young (4- to 6-month-old) and old (24-month-old) male Fischer 344 rats. βAR density (Bmax) in liver membranes was measured by a radioligand receptor binding assay using the receptor subtype nonselective βAR antagonist 125I-pindolol as the radioligand. Steady-state levels of β2AR mRNA in rat liver were measured by Northern blot analysis; because of the low abundance of β1AR and β3AR mRNA in rat liver, the expressions of these genes were measured by a semiquantitative RT-PCR or an RT-PCR. Scatchard analysis of saturation binding curves of the binding assay confirmed an age-related increase in Bmax (young: 7.1?±?0.8?fmol/mg protein vs. old: 18.1?±?4.3?fmol/mg protein). No age-related differences were found in the levels of β2AR mRNA. However, semiquantitative RT-PCR revealed an approximately twofold increase in β1AR mRNA level between young and old rats (P?<?0.05). β1AR mRNA levels were also correlated with Bmax values for 125I-pindolol binding sites in individual rats (r = 0.67; P?=?0.012). β3AR mRNA, which was demonstrable in rat white adipose tissue by RT-PCR, was generally not detected in livers from young or old rats, with the exception of two old rats with the highest Bmax. These results suggest that an age-related increase of β1AR gene expression contributes to increased βAR density and β adrenergic responsiveness in rat liver during aging. 相似文献
102.
《Journal of receptor and signal transduction research》2013,33(2):102-113
A2A adenosine receptor (AR) antagonists play an important role in neurodegenerative diseases like Parkinson’s disease. A 3D-QSAR study of A2A AR antagonists, was taken up to design best pharmacophore model. The pharmacophoric features (ADHRR) containing a hydrogen bond acceptor (A), a hydrogen bond donor (D), a hydrophobic group (H) and two aromatic rings (R), is projected as the best predictive pharmacophore model. The QSAR model was further treated as a template for in silico search of databases to identify new scaffolds. The binding patterns of the leads with A2A AR are analysed using docking studies and novel potent ligands of A2A AR are projected. 相似文献
103.
《Journal of receptor and signal transduction research》2013,33(1):37-40
AbstractInsulin plays an important role in various metabolic as well as anabolic actions in cells, including osteoblast cells. In the present study, we explored to determine if insulin receptor could associate with syndecan-1 in response to insulin and such association could lead to the activation of subsequent ERK I/II and alkaline phosphatase (ALP) in osteoblast cells. Insulin rapidly induces the association of insulin receptor with syndecan-1. Synstatin is a specific peptide inhibitor that blocks the binding of syndecan-1 to integrate. In the presence of synstatin, insulin-stimulated ERK I/II activation was dramatically inhibited, suggesting that syndecan-1/integrin interaction is essential in the activation of ERK I/II by insulin. Pretreatment of synstatin also inhibited the insulin-stimulated ALP activity. Taken together, these results suggest that insulin stimulates the association of insulin receptor with syndecan-1 and the complex formation of syndecan-1 and integrin could play an important role in ERK I/II–ALP signaling pathway in osteoblast cells. 相似文献
104.
《Journal of receptor and signal transduction research》2013,33(2):79-88
AbstractA cluster of hydrophobic amino acids at the cytoplasmic end of trans-membranal helix III (TM-III) is a common feature among class-A of G protein-coupled receptors (GPCR). We mutagenized alanine 1593.53 to glutamic acid and isoleucine1603.54 to arginine (A159E/I160R) in TM-III of the human ß1-adrenergic receptor (ß1-AR) to disrupt the function of the hydrophobic cluster. Structurally, the combined mutations of A159E/I160R caused an almost 90° tilt in the rotation of Arg1563.50 in the E/DRY motif of TM-III and displaced Tyr1663.60 in intracellular loop 2. The A159E/I160R ß1-AR was uncoupled from Gs as determined by cyclic AMP/adenylyl cyclase assays and by FRET-based proximity measurements between the ß1-AR and Gsα. Isoproterenol induced ß-arrestin trafficking in cells expressing both the wild-type ß1-AR and the A159E/I160R ß1-AR. Isoproterenol markedly increased the phosphorylation of ERK1/2 in cells expressing the WT ß1-AR and this effect was dependent on the activation of the Gs-cyclic AMP-dependent protein kinase?→?Rap?→?B-raf axis. However, in cells bearing the A159E/I160R ß1-AR, isoproterenol failed to increase the phosphorylation of ERK1/2. These results indicate that mutations in the Gsα-binding pocket of the GPCR interfered with receptor coupling to Gs and with its downstream signaling cascades. 相似文献
105.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):832-844
This study aimed to identify the docking and molecular mechanics-generalized born surface area (MM-GBSA) re-scoring parameters which can correlate the binding affinity and selectivity of the ligands towards oestrogen receptor β (ERβ). Three different series of ERβ ligands were used as dataset and the compounds were docked against ERβ (protein data bank (PDB) ID: 1QKM) using Glide and ArgusLab. Glide docking showed superior results when compared with ArgusLab. Docked poses were then rescored using Prime-MM-GBSA to calculate free energy binding. Correlations were made between observed activities of ERβ ligands with computationally predicted values from docking, binding energy parameters. ERβ ligands experimental binding affinity/selectivity did not correlate well with Glide and ArgusLab score. Whereas calculated Glide energy (coulomb-van der Waal interaction energy) correlated significantly with binding affinity of ERβ ligands (r2?=?0.66). MM-GBSA re-scoring showed correlation of r2?=?0.74 with selectivity of ERβ ligands. These results will aid the discovery of novel ERβ ligands with isoform selectivity. 相似文献
106.
107.
《Cell communication & adhesion》2013,20(5-6):146-153
AbstractThe receptor protein tyrosine phosphatase T PTPρ is the most frequently mutated tyrosine phosphatase in human cancer. PTPρ mediates homophilic cell-cell aggregation. In its extracellular region, PTPρ has cell adhesion molecule–like motifs, including a MAM domain, an immunoglobulin domain, and four fibronectin type III (FNIII) repeats. Tumor-derived mutations have been identified in all of these extracellular domains. Previously, the authors determined that tumor-derived mutations in the MAM and immunoglobulin domains of PTPρ reduce homophilic cell-cell aggregation. In this paper, the authors describe experiments in which the contribution of the FNIII repeats to PTPρ-mediated cell-cell adhesion was evaluated. The results demonstrate that deletion of the FNIII repeats of PTPρ result in defective cell-cell aggregation. Furthermore, all of the tumor-derived mutations in the FNIII repeats of PTPρ also disrupt cell-cell aggregation. These results further support the hypothesis that mutational inactivation of PTPρ may lead to cancer progression by disrupting cell-cell adhesion. 相似文献
108.
109.
《Fly》2013,7(4):200-205
AbstractAll species of animals display aggression in order to obtain resources such as territories, mates, or food. Appropriate displays of aggression rely on the correct identification of a potential competitor, an evaluation of the environmental signals, and the physiological state of the animal. With a hard-wired circuitry involving fixed numbers of neurons, neuromodulators like serotonin offer adaptive flexibility in behavioral responses without changing the “hard-wiring”. In a recent report, we combined intersectional genetics, quantitative behavioral assays and morphological analyses to identify single serotonergic neurons that modulate the escalation of aggression. We found anatomical target areas within the brain where these neurons appear to form synaptic contacts with 5HT1A receptor-expressing neurons, and then confirmed the likelihood of those connections on a functional level. In this Extra View article, we offer an extended discussion of these recent findings and elaborate on how they can link a cellular and functional mapping of an aggression-regulating circuit at a single-cell resolution level. 相似文献
110.
《Channels (Austin, Tex.)》2013,7(3):193-202
Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency. PRL also influences neuronal functions via activation of certain neurons, resulting in Ca2+ influx and/or electrical firing with subsequent release of neurotransmitters. Although PRL was identified almost a century ago, very little specific information is known about how PRL regulates neuronal functions. Nevertheless, important initial steps have recently been made including the identification of PRL-induced transient signaling pathways in neurons and the modulation of neuronal transient receptor potential (TRP) and Ca2+-dependent K+ channels by PRL. In this review, we summarize current knowledge and recent progress in understanding the regulation of neuronal excitability and channels by PRL. 相似文献