Abstract:
:Regulator of G protein signaling (RGS) proteins accelerate the endogenous GTPase activity of Galpha(i/o) proteins to increase the rate of deactivation of active Galpha-GTP and Gbetagamma signaling molecules. Previous studies have suggested that RGS proteins are more effective on less efficiently coupled systems such as with partial agonist responses. To determine the role of endogenous RGS proteins in functional responses to mu-opioid agonists of different intrinsic efficacy, Galpha(i/o) subunits with a mutation at the pertussis toxin (PTX)-sensitive cysteine (C351I) and with or without a mutation at the RGS binding site (G184S) were stably expressed in C6 glioma cells expressing a mu-opioid receptor. Cells were treated overnight with PTX to inactivate endogenous G proteins. Maximal inhibition of forskolin-stimulated adenylyl cyclase by the low-efficacy partial agonists buprenorphine and nalbuphine was increased in cells expressing RGS-insensitive Galpha(o)(CIGS), Galpha(i2)(CIGS), or Galpha(i3)(CIGS) compared with their Galpha(CI) counterparts, but the RGS-insensitive mutation had little or no effect on the maximal inhibition by the higher efficacy agonists DAMGO and morphine. The potency of all the agonists to inhibit forskolin-stimulated adenylyl cyclase was increased in cells expressing RGS-insensitive Galpha(o)(CIGS), Galpha(i2)(CIGS), or Galpha(i3)(CIGS), regardless of efficacy. These data are comparable with predictions based on a collision coupling model. In this model, the rate of G protein inactivation, which is modulated by RGS proteins, and the rate of G protein activation, which is affected by agonist intrinsic efficacy, determine the maximal agonist response and potency at adenylyl cyclase under steady state conditions.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Clark MJ,Linderman JJ,Traynor JRdoi
10.1124/mol.107.043547subject
Has Abstractpub_date
2008-05-01 00:00:00pages
1538-48issue
5eissn
0026-895Xissn
1521-0111pii
mol.107.043547journal_volume
73pub_type
杂志文章abstract::Pertussis toxin (PTX) ADP-ribosylates alpha subunits of GTP-binding proteins (G proteins) when they are in association with beta gamma dimers, and free alpha subunits are thought not to be substrates under standard assay conditions. We now report the rather unexpected discovery that synthetic peptides encompassing the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-11-01 00:00:00
abstract::Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentra...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-04-01 00:00:00
abstract::The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obsc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.088096
更新日期:2013-11-01 00:00:00
abstract::Receptors for the serine protease thrombin and for lysophospholipids are coupled to G proteins and control a wide range of cellular functions, including mitogenesis. Activators of these receptors are present in blood, and can enter the brain during central nervous system (CNS) injury. Reactive astrogliosis, a prominen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.5.1199
更新日期:2003-11-01 00:00:00
abstract::Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in dif...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.071290
更新日期:2011-06-01 00:00:00
abstract::The binding of [3H]Hspiroperidol to D2 dopaminergic receptors in rat striatum was compared to the binding of [3H]dopamine to its binding sites. Both radioligands labeled apparently homogeneous populations of high affinity, stereoselective, saturable sites, determined from analysis of saturation isotherms. [3H]Spiroper...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-11-01 00:00:00
abstract::Neurotrophins are a family of secreted proteins that play an important role in the development, differentiation, and survival of neurons. Studies also suggest that aberrant neurotrophin signaling may play a role in processes underlying disease states such as schizophrenia, Alzheimer's disease, and depression. Whereas ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.020255
更新日期:2006-04-01 00:00:00
abstract::A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.065102
更新日期:2010-10-01 00:00:00
abstract::We reported previously the formation of a glutathionyl conjugate of the active metabolite (AM) of clopidogrel and the covalent modification of a cysteinyl residue of human cytochrome P450 2B6 in a reconstituted system (Mol Pharmacol 80:839-847, 2011). In this work, we extended our studies of the metabolism of clopidog...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.079061
更新日期:2012-08-01 00:00:00
abstract::Although α7 nicotinic acetylcholine receptors are considered potentially important therapeutic targets, the development of selective agonists has been stymied by the α7 receptor's intrinsically low probability of opening (P(open)) and the concern that an agonist-based therapeutic approach would disrupt endogenous chol...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.074302
更新日期:2011-12-01 00:00:00
abstract::ATP-gated purinergic receptors (P2XRs) are a family of cation-permeable channels that conduct Ca(2+) and facilitate voltage-sensitive Ca(2+) entry in excitable cells. To study Ca(2+) signaling by P2XRs and its dependence on voltage-sensitive Ca(2+) influx, we expressed eight cloned P2XR subtypes individually in gonado...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.5.936
更新日期:2000-11-01 00:00:00
abstract::Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phospho...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.041160
更新日期:2008-03-01 00:00:00
abstract::Iodonium inhibition of the flavoenzymes neutrophil NADPH oxidase and cytochrome P450 reductase has been suggested to require reductive metabolism of the inhibitor to a phenyl radical. Inhibition would ultimately result from covalent attachment of phenyl radicals to either the flavin cofactor or adjacent amino acid sid...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-10-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-05-01 00:00:00
abstract::A central axiom of ligand-receptor theory is that agonists bind more tightly to active than to inactive receptors. However, measuring agonist affinity in inactive receptors is confounded by concomitant activation. We identified a cysteine substituted mutant γ-aminobutyric acid type A (GABAA) receptor with unique chara...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.084558
更新日期:2013-06-01 00:00:00
abstract::The thiazolidinediones are a class of antidiabetic compounds that increase the sensitivity of target tissues to insulin. An earlier study has shown that these compounds enhance the insulin-stimulated differentiation of 3T3-L1 cells and up-regulate expression of differentiation-dependent genes. We have observed that th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::Nicotine can enhance working memory and attention. Activation of both alpha7 and beta2(*) nicotinic acetylcholine receptors (nAChRs) in the prefrontal cortex (PFC) has been implicated in these processes. The ability of presynaptic nAChRs to modulate neurotransmitter release, notably glutamate release, is postulated to...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.046623
更新日期:2008-08-01 00:00:00
abstract::PDE4A11 is a novel cAMP-specific phosphodiesterase that is conserved in humans, mouse, rat, pig, and bat. Exon-1(4A11) encodes its unique, 81 amino acid N-terminal region. Reverse-transcriptase polymerase chain reaction performed across the splice junction, plus identification of expressed sequence tags, identifies PD...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.009423
更新日期:2005-06-01 00:00:00
abstract::The levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transfer...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-10-01 00:00:00
abstract::Camptothecin (CPT) is an effective chemotherapeutic agent for treatment of patients with cancer. The mechanisms underlying CPT-mediated responses in cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug sensitivity. However, the interaction between camptothecin and miRN...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.076794
更新日期:2012-04-01 00:00:00
abstract::Immune-mediated drug hypersensitivity reactions (IDHRs) represent a significant problem due to their unpredictable and severe nature, as well as the lack of understanding of the pathogenesis. Sulfamethoxazole (SMX), a widely used antibiotic, has been used as a model compound to investigate the underlying mechanism of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.043273
更新日期:2008-06-01 00:00:00
abstract::Autophagy is the process by which cellular material is delivered to lysosomes for degradation and recycling. There are three different types of autophagy, but macroautophagy, which involves the formation of double membrane vesicles that engulf proteins and organelles that fuse with lysosomes, is by far the most studie...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.114.091850
更新日期:2014-06-01 00:00:00
abstract::A cDNA encoding the human liver phenol-sulfating form of phenol sulfotransferase (P-PST) has been isolated and characterized from a lambda Uni-Zap XR human liver cDNA library. P-PST is the major form of phenol sulfotransferase involved in drug and xenobiotic metabolism in human liver. P-PST is also responsible for the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-01-01 00:00:00
abstract::Identifying novel mechanisms to enhance glucagon-like peptide-1 (GLP-1) receptor signaling may enable nascent medicinal chemistry strategies with the aim of developing new orally available therapeutic agents for the treatment of type 2 diabetes mellitus. Therefore, we tested the hypothesis that selectively modulating ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080432
更新日期:2012-12-01 00:00:00
abstract::As noted previously, in N1E-115 neuroblastoma cells, carbamylcholine, a muscarinic cholinergic agonist, increased cGMP over 15-fold and decreased basal and prostaglandin E1 (PGE1)-stimulated cAMP content. In contrast to the stimulatory effects of PGE1 on cAMP, which were immediate, the carbamylcholine-induced decrease...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-08-01 00:00:00
abstract::The mammalian copper transporter 1 (CTR1) is responsible for the uptake of copper from the extracellular space. In this study, we used an isogenic pair of CTR1(+/+) and CTR1(-/-) mouse embryo fibroblasts to examine the contribution of CTR1 to the influx of cisplatin (DDP), carboplatin (CBDCA), oxaliplatin (L-OHP), and...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.052381
更新日期:2009-02-01 00:00:00
abstract::Direct gastric mucosal cell damage mediated by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. We recently suggested that this direct cytotoxicity of NSAIDs is caused by their membrane-permeabilization activity. Geranylgeranylacetone (GGA), a clinically used...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.015784
更新日期:2005-10-01 00:00:00
abstract::We investigated the roles of cyclic GMP and cyclic AMP in the inhibition of rabbit platelet aggregation and degranulation by two nitrovasodilators, sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1; the active metabolite of molsidomine), with particular reference to the synergistic interaction of these dru...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-05-01 00:00:00
abstract::Cu/Zn-superoxide dismutase (SOD)-accelerated oxidation of the benzene metabolite 1,4-hydroquinone (HQ) results in the enhanced formation of semiquinone anion radicals, electrophilic 1,4-benzoquinone (BQ), and H202. We selected bone marrow stromal cells and phiX-174 double stranded plasmid DNA as model systems to inves...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-03-01 00:00:00