共查询到20条相似文献,搜索用时 31 毫秒
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Harold H Bach IV Yee M Wong Abhishek Tripathi Amanda M Nevins Richard L Gamelli Brian F Volkman Kenneth L Byron Matthias Majetschak 《Molecular medicine (Cambridge, Mass.)》2014,20(1):435-447
Chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor (ACKR) 3 ligands have been reported to modulate cardiovascular function in various disease models. The underlying mechanisms, however, remain unknown. Thus, it was the aim of the present study to determine how pharmacological modulation of CXCR4 and ACKR3 regulate cardiovascular function. In vivo administration of TC14012, a CXCR4 antagonist and ACKR3 agonist, caused cardiovascular collapse in normal animals. During the cardiovascular stress response to hemorrhagic shock, ubiquitin, a CXCR4 agonist, stabilized blood pressure, whereas coactivation of CXCR4 and ACKR3 with CXC chemokine ligand 12 (CXCL12), or blockade of CXCR4 with AMD3100 showed opposite effects. While CXCR4 and ACKR3 ligands did not affect myocardial function, they selectively altered vascular reactivity upon α1-adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced α1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized α1-AR-mediated vasoconstriction. The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically. CXCR4 and ACKR3 ligands did not affect vasoconstriction upon activation of voltage-operated Ca2+ channels or endothelin receptors. Effects of CXCR4 and ACKR3 agonists on vascular α1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate α1-AR reactivity in vascular smooth muscle and regulate hemodynamics in normal and pathological conditions. Our observations point toward CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure. 相似文献
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Prolonged opioid treatment leads to a comprehensive cellular adaptation mediated by opioid receptors, a basis to understand
the development of opioid tolerance and dependence. However, the molecular mechanisms underlying opioid-induced cellular adaptation
remain obscure. Recent advances in opioid receptor trafficking and signaling in cells have extensively increased our insight
into the network of intracellular signal integration. This review focuses on those important intracellular biochemical processes
that play critical roles in the development of opioid tolerance and dependence after opioid receptor activation, and tries
to explain what happens after opioid receptor activation, and how the cellular adaptation develops from cell membrane to nucleus.
Decades of research have delineated a network on opioid receptor trafficking and signaling, but the challenge remains to explain
opioid tolerance and dependence from a single cellular signal network. 相似文献
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Docking methodology aims to predict the experimental binding modes and affinities of small molecules within the binding site of particular receptor targets and is currently used as a standard computational tool in drug design for lead compound optimisation and in virtual screening studies to find novel biologically active molecules. The basic tools of a docking methodology include a search algorithm and an energy scoring function for generating and evaluating ligand poses. In this review, we present the search algorithms and scoring functions most commonly used in current molecular docking methods that focus on protein–ligand applications. We summarise the main topics and recent computational and methodological advances in protein–ligand docking. Protein flexibility, multiple ligand binding modes and the free-energy landscape profile for binding affinity prediction are important and interconnected challenges to be overcome by further methodological developments in the docking field. 相似文献
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Unzicker C Erberich H Moldrich G Woldt H Bulla J Mechoulam R Ehrenreich H Sirén AL 《Neurochemical research》2005,30(10):1305-1309
Endothelin (ETB)-receptors mediate anti-apoptotic actions. Lack of functional ETB-receptors leads to increased neuronal apoptosis
in the hippocampus. The increased apoptosis must be compensated by other mechanisms, however, as ETB-deficient rats display
normal overall brain morphology. To illuminate on brain plasticity in ETB-receptor deficiency, we studied the expression and
function of another neuroprotective system, the cannabinoid CB1-receptors, in ETB-deficient hippocampus. We show that CB1
expression in hippocampus increases postnatally in all rats but that the increase in CB1-receptor expression is significantly
higher in ETB-deficient compared to wildtype littermates. Neuronal apoptosis decreases during brain maturation but remains
on a significantly higher level in the ETB-deficient compared to wildtype dentate. When investigating survival of hippocampal
neurons in culture, we found significant protection against hypoxia-induced cell death with CB1-analogs (noladin, (9-tetrahydrocannabinol)
only in ETB-deficient neurons. We suggest that CB1-receptor upregulation in the ETB-mutant hippocampus reflects an attempt
to compensate for the lack of ETB-receptors.
Special issue dedicated to Dr. Bernd Hamprecht 相似文献
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Characteristics of Non-opioid β-Endorphin Receptor 总被引:4,自引:0,他引:4
Navolotskaya EV Kovalitskaya YA Zolotarev YA Kolobov AA Kampe-Nemm EA Malkova NV Yurovsky VV Lipkin VM 《Biochemistry. Biokhimii?a》2004,69(4):394-400
Tritium-labeled selective agonist of non-opioid beta-endorphin receptor, the decapeptide immunorphine ([3H]SLTCLVKGFY) with specific activity of 24 Ci/mmol has been prepared. By its use, non-opioid beta-endorphin receptors were revealed and characterized on mouse peritoneal macrophages and rat myocardium, spleen, adrenal, and brain membranes. The non-opioid beta-endorphin receptor of macrophages has in addition to immunorphine (Kd of the [3H]immunorphine-receptor complex was 2.4 +/- 0.1 nM) and beta-endorphin (Ki of the [3H]immunorphine specific binding was 2.9 +/- 0.2 nM) a high affinity for Fc-fragment of human IgG1, pentarphine (VKGFY), cyclopentarphine [cyclo(VKGFY)], and [Pro3]pentarphine (VKPFY) (Ki values were 0.0060 +/- 0.0004, 2.7 +/- 0.2, 2.6 +/- 0.2, and 2.8 +/- 0.2 nM, respectively) and is insensitive to naloxone and [Met5]enkephalin (Ki > 100 microM). Treatment of macrophages with trypsin resulted in the loss of their ability for the specific binding of [3H]immunorphine. Values of the specific binding of 8.4 nM [3H]immunorphine to rat adrenal, spleen, myocardium, and brain membranes were determined to be 1146.0 +/- 44.7, 698.6 +/- 28.1, 279.1 +/- 15.4, and 172.2 +/- 1.8 fmol/mg protein, respectively. Unlabeled beta-endorphin, pentarphine, [Pro3]pentarphine, cyclopentarphine, cyclodipentarphine [cyclo(VKGFYVKGFY)], and Fc-fragment of IgG1 inhibited the binding of [3H]immunorphine to membranes from these organs. No specific binding of [3H]immunorphine to rat liver, lung, kidney, and intestine membranes was found. 相似文献
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Glucose metabolism is under the cooperative regulation of both insulin receptor (IR) and β2-adrenergic receptor (β2AR), which represent the receptor tyrosine kinases (RTKs) and seven transmembrane receptors (7TMRs), respectively. Studies demonstrating cross-talk between these two receptors and their endogenous coexpression have suggested their possible interactions. To evaluate the effect of IR and prospective heteromerization on β2AR properties, we showed that IR coexpression had no effect on the ligand binding properties of β2AR; however, IR reduced β2AR surface expression and accelerated its internalization. Additionally, both receptors displayed a similar distribution pattern with a high degree of colocalization. To test the possible direct interaction between β2AR and IR, we employed quantitative BRET2 saturation and competition assays. Saturation assay data suggested constitutive β2AR and IR homo- and heteromerization. Calculated acceptor/donor (AD50) values as a measure of the relative affinity for homo- and heteromer formation differed among the heteromers that could not be explained by a simple dimer model. In heterologous competition assays, a transient increase in the BRET2 signal with a subsequent hyperbolical decrease was observed, suggesting higher-order heteromer formation. To complement the BRET2 data, we employed the informational spectrum method (ISM), a virtual spectroscopy method to investigate protein-protein interactions. Computational peptide scanning of β2AR and IR identified intracellular domains encompassing residues at the end of the 7th TM domain and C-terminal tail of β2AR and a cytoplasmic part of the IR β chain as prospective interaction domains. ISM further suggested a high probability of heteromer formation and homodimers as basic units engaged in heteromerization. In summary, our data suggest direct interaction and higher-order β2AR:IR oligomer formation, likely comprising heteromers of homodimers. 相似文献
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Jill Coates Mark F. Gurden Carol Harris Ian Kennedy Michael J. Sheehan Peter Strong 《Nucleosides, nucleotides & nucleic acids》2013,32(9):1953-1976
Abstract Considerable progress has been made in our understanding of the diversity of adenosine receptors during the last decade, with the cloning of the orphan receptors RDC7 and RDC8 (1), and their subsequent characterisation as canine A1 and A2 receptors respectively (2,3), in the late 1980s. The principal objective of this review is to produce an integrated view of adenosine receptor classification, using the important observations from studies of molecular biology, receptor binding characteristics and functional pharmacology. 相似文献
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The study addressed to resolve the mechanism involved in cholesteroldependent regulation of giardia encystation process, revealed that (a) the trophozoites have the ability to express genes coding for receptorCk and sterol element binding protein (SREBP); (b) inhibition of cholesterol dependent activation of receptorCk results in the upregulation of CWP1 gene expression leading to encystation process. Based upon these findings, we propose that receptorCk dependent signalling is responsible for the regulation of giardia encystation process by cholesterol. 相似文献
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《Journal of receptor and signal transduction research》2013,33(1):75-85
AbstractThe β2-adrenergic receptor (β2AR) couples to Gs, activating adenylyl cyclase (AC) and increasing cAMP. Such signaling undergoes desensitization with continued agonist exposure. β2AR also couple to Gi after receptor phosphorylation by the cAMP dependent protein kinase A, but the efficiency of such coupling is not known. Given the PKA dependence of β2AR-Gi coupling, we explored whether this may be a mechanism of agonist-promoted desensitization. HEK293 cells were transfected to express β2AR or β2AR and Giα2, and then treated with vehicle or the agonist isoproterenol to evoke agonist-promoted β2AR desensitization. Membrane AC activities showed that Giα2 overexpression decreased basal levels, but the fold-stimulation of the AC over basal by agonist was not altered. However, with treatment of the cells with isoproterenol prior to membrane preparation, a marked decrease in agonist-stimulated AC was observed with the cells overexpressing Giα2. in the absence of such overexpression, β2AR desensitization was 23 ± 7%, while with 5-fold Giα2 overexpression desensitization was 58 ± 5% (p<0.01, n=4). the effect of Gi on desensitization was receptor-specific, in that forskolin responses were not altered by Giα2 overexpression. Thus, acquired β2AR coupling to Gi is an important mechanism of agonist-promoted desensitization, and pathologic conditions that increase Gi levels contribute to β2AR dysfunction. 相似文献
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Timothy H. Goldsmith 《The Journal of general physiology》1965,49(2):265-287
(1) The compound eye of Musca exhibits characteristics which have heretofore frequently been considered evidence for color receptors: (a) The spectral sensitivity curve has several peaks whose relative heights can be altered by selective adaptation to colored lights, and (b) the shape of the retinal action potential varies with wave length. (2) The action spectrum for the red enhancement of on and off responses is compared with the "red receptor" calculated by Mazokhin-Porshnyakov from colorimetric data obtained in rapid color substitutions. Both have maxima at 615 to 620 mµ and appear to be different expressions of the same phenomenon. (3) A red receptor is absent. The evidence which suggests different types of receptors in the region 500 to 700 mµ can be accounted for by variations in the numbers of receptors stimulated. In red light there is a recruitment of additional ommatidia caused by leakage of long wave lengths through the pigment screen, and this spatial summation potentiates the on and off responses. The principal evidence is: (a) a white eye mutant which has no accessory screening pigments also lacks the peak of sensitivity in the red, even when adapted to violet light; (b) white-eyed flies give identical responses with large on and off effects at all wave lengths from 500 to 700 mµ; and (c) reducing the number of excited ommatidia by decreasing the size of the test spot makes the on and off transients smaller relative to the receptor component. 相似文献
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Xin Ge Yu Qiu Horace H. Loh Ping-Yee Law 《The Journal of biological chemistry》2009,284(52):36521-36534
The lipid raft location of μ-opioid receptor (MOR) determines the receptor activities. However, the manner in which MOR is anchored within the lipid rafts is undetermined. Using the targeted proteomic approach and mass spectrometry analyses, we have identified GRIN1 (G protein-regulated inducer of neurite outgrowth 1) can tether MOR with the G protein α-subunit and subsequently regulate the receptor distribution within the lipid rafts. Glutathione S-transferase fusion pulldown and receptor mutational analyses indicate that GRIN1-MOR interaction involves a receptor sequence 267GSKEK271 within the MOR third intracellular loop that is not involved in Gα interaction. The GRIN1 domains involved in MOR interaction are also distinct from those involved in Gα interaction. Pertussis toxin pretreatment reduced the amount of GRIN1 co-immunoprecipitated with MOR but not the amount with Gα. Furthermore, overexpression of GRIN1 significantly enhanced the amount of MOR in lipid raft and the receptor signaling magnitude as measured by Src kinase activation. Such increase in MOR signaling was demonstrated further by determining the GRIN1-dependent pertussis toxin-sensitive neurite outgrowth. In contrast to minimal neurite outgrowth induced by etorphine in control neuroblastoma N2A cells, overexpression of GRIN1 resulted in the increase in etorphine- and non-morphine-induced neurite outgrowth in these cells. Knocking down endogenous GRIN1 by small interfering RNA attenuated the agonist-induced neurite outgrowth. Disrupting lipid raft by methyl-β-cyclodextrin also blocked neurite outgrowth. Hence, by tethering Gα with MOR, GRIN1 stabilizes the receptor within the lipid rafts and potentiates the receptor signaling in the neurite outgrowth processes. 相似文献
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Dieudonnée Togbe Paulo Loureiro de Sousa Mathilde Fauconnier Victorine Boissay Lizette Fick Stefanie Scheu Klaus Pfeffer Robert Menard Georges E. Grau Bich-Thuy Doan Jean Claude Beloeil Laurent Renia Anna M. Hansen Helen J. Ball Nicholas H. Hunt Bernhard Ryffel Valerie F. J. Quesniaux 《PloS one》2008,3(7)