Abstract:
:Endothelin-1 (ET) and ATP mobilize Ca2+ in rat C6 glioma cells by stimulating phosphoinositide turnover. Both agents also inhibit adenylyl cyclase (AC) activity in C6 glioma cells. The goal of this study was to characterize the molecular mechanisms responsible for the inhibition of AC activity. The administration of either ET, ATP, A23187, or thapsigargin to cells simultaneously with isoproterenol for 5 min inhibited isoproterenol-stimulated cAMP synthesis by a maximum of 60%, 91%, 65%, and 68%, respectively. Pretreatment of cells with pertussis toxin (PTX) did not alter the inhibitory effects of A23187 or thapsigargin, whereas the inhibitory effects of ET or ATP were completely eliminated. Removal of extracellular Ca2+ and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid acetoxymethyl ester treatment failed to affect the inhibition caused by ET or ATP, whereas the inhibition caused by A23187 or thapsigargin was completely eliminated in Ca(2+)-free medium and was attenuated by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester treatment. The inhibition by both receptor agonists in the earlier phase (30 sec) of the AC reaction was, however, reduced by using either Ca(2+)-free medium or PTX pretreatment. The administration of 3-isobutyl-1-methylxanthine or Ro 20-1724 suggested that the inhibitory effects of A23187 and thapsigargin were partially due to Ca(2+)-dependent stimulation of PDE activity. Short term treatment with phorbol-12-myristate-13-acetate (PMA) had no effect on isoproterenol-stimulated AC activity. However, the inhibition of cAMP induced by ET or ATP, but not by A23187 or thapsigargin, was diminished by PMA, suggesting that the receptor signal via Gi was blocked by PMA treatment. The antagonistic effect of PMA was blocked by staurosporine. All four agents still inhibited AC activity in cells that had been treated with PMA for 24 hr to deplete protein kinase C. ET produced an additional decrease in AC activity in cells that had been treated with a maximally effective concentration of A23187 or thapsigargin. The ET- or ATP-induced decrease in cAMP levels showed homologous desensitization. These results demonstrate that ETZ receptors and ATP receptors in C6 glioma cells inhibit AC activity primarily by interaction with a PTX-sensitive G(i) and partially by elevation of [Ca(2+)]. Protein kinase C activation is not responsible for agonist-induced inhibition of AC but appears to uncouple the G(i)/AC system activated by ET or ATP.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Lin WW,Chuang DMsubject
Has Abstractpub_date
1993-07-01 00:00:00pages
158-65issue
1eissn
0026-895Xissn
1521-0111journal_volume
44pub_type
杂志文章abstract::G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacolo...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.115.098509
更新日期:2015-10-01 00:00:00
abstract::Reconstitution experiments with purified components reproduce the basic characteristics of receptor/G protein coupling, i.e., GTP-sensitive high affinity agonist binding and receptor-promoted GTP binding. However, the interaction of agonists with the A1 adenosine receptor in rat and bovine but not human brain membrane...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::Bryostatin 1 and phorbol-12-myristate-13-acetate (PMA) are both potent activators of protein kinase C (PKC), although in primary mouse keratinocytes bryostatin 1 does not induce differentiation and blocks PMA-induced differentiation. We report here that in primary mouse keratinocytes PMA caused translocation of PKC-ep...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-11-01 00:00:00
abstract::The interaction of [3H]acetylcholine ([3H]AcCh) with the muscarinic receptor was studied in seven distinct rat brain regions and in heart atrium by employing 10 microM atropine to define specific binding. The specific binding exhibited by the labeled neurotransmitter was found to be sensitive to muscarinic but not to ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-09-01 00:00:00
abstract::CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modificatio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.117.108225
更新日期:2017-08-01 00:00:00
abstract::Although both second messenger response systems are fully functional in both cell lines, activation of muscarinic cholinergic receptors only results in inhibition of adenylate cyclase in NG108-15 neuroblastoma X glioma cells and stimulation of phosphoinositide hydrolysis in 1321N1 human astrocytoma cells. Muscarinic r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-10-01 00:00:00
abstract::Propofol, etomidate, and barbiturate anesthetics are allosteric coagonists at pentameric α1β3γ2 GABAA receptors, modulating channel activation via four biochemically established intersubunit transmembrane pockets. Etomidate selectively occupies the two β+/α- pockets, the barbiturate photolabel R-5-allyl-1-methyl-5-(m-...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.118.115048
更新日期:2019-04-01 00:00:00
abstract::Recent reports regarding the significance of chemokine receptors in disease have put a spotlight on atypical chemokine receptor 3 (ACKR3). This atypical chemokine receptor is overexpressed in numerous cancer types and has been involved in the modulation of tumor cell proliferation and migration, tumor angiogenesis, or...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.118.115279
更新日期:2019-12-01 00:00:00
abstract::AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors; however, the signaling profile of AM1710 re...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.118.113233
更新日期:2019-02-01 00:00:00
abstract::The clinical abuse of methamphetamine (METH) is a major concern because it can cause long-lasting neurodegenerative effects in humans. Current concepts of the molecular mechanisms underlying these complications have centered on the formation of reactive oxygen species. Herein, we provide cDNA microarray evidence that ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.5.1124
更新日期:2002-05-01 00:00:00
abstract::The ATP signaling mechanism in neuroblastoma x glioma hybrid NG108-15 cells differentiated by exposure to dibutyryl-cAMP was characterized. In cells loaded with fura-2, ATP rapidly raised the cytosolic Ca2+ concentration ([Ca2+]i); the magnitude of the rise was inversely proportional to the extracellular Na+ concentra...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::We compared the efficiencies with which human alpha 1-adrenergic receptor (AR) subtypes activate inositol phosphate (InsP) formation and increase intracellular Ca2+ in transfected cell lines. Expression of human alpha 1a-, alpha 1b-, and alpha 1d-AR cDNAs under the repressible control of anhydrotetracycline in human e...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-11-01 00:00:00
abstract::EM-652 (SCH 57068) is a new orally active antiestrogen that demonstrates pure antagonistic effects in the mammary gland and endometrium. In vivo studies have shown that EM-652 is primarily glucuronidated at the 7-hydroxy position in rats and that the metabolite is present in the plasma of female monkeys and human subj...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.3.636
更新日期:2001-03-01 00:00:00
abstract::Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipop...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.046847
更新日期:2008-07-01 00:00:00
abstract::Prenatal exposure to diethylstilbestrol (DES) is known to cause an increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in the thymus. In the current study, we investigated if such ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.114.096743
更新日期:2015-05-01 00:00:00
abstract::In Rat-1 fibroblasts, endothelin-1 and a protein kinase C-stimulating phorbol ester stimulated extracellular signal-regulated kinase (ERK), whereas phenylephrine, acting at stably transfected human alpha1A-adrenoceptors, inhibited basal and endothelin-1- and phorbol ester-stimulated ERK. On the other hand, phenylephri...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.54.5.755
更新日期:1998-11-01 00:00:00
abstract::The ligand specificity of rat adenohypophyseal vasopressin receptors was directly compared to that of peripheral receptors of the V1 and V2 types. For this purpose a series of 15 recently designed vasopressin antagonists was used. The affinities of these antagonists for rat adenohypophyseal membranes were deduced from...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-08-01 00:00:00
abstract::P2X receptors are trimeric membrane proteins. When they bind extracellular ATP, a conformational change occurs that opens a transmembrane ion channel. The ATP-binding pocket is formed in a cleft between two subunits, and a critical amino acid residue for ATP contact is Lys⁶⁹ (P2X2 numbering). In the present work, we s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080903
更新日期:2012-10-01 00:00:00
abstract::The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27 and PACAP38, are two neuropeptide hormones related to the vasoactive intestinal peptide/secretin/ glucagon family of peptides. PACAP receptors that are positively coupled to adenylyl cyclase and phospholipase C have been identified in culture...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-07-01 00:00:00
abstract::The selective inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 involved in the 21-hydroxylation of progesterone has been investigated. Five derivatives each of pregnenolone and progesterone were prepared, in which the methylketo substituent of the 17 beta-position was replaced by ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-01-01 00:00:00
abstract::Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression of gamma-aminobutyrate (GABA) channels easily accessible for current measurements using the voltage clamp technique. The effect of the anthelmintic natural product avermectin B1a on the GABA current was studied quantitatively. ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-12-01 00:00:00
abstract::Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malig...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.091439
更新日期:2014-08-01 00:00:00
abstract::We have recently demonstrated that the alpha 2-adrenergic radioligand [3H]idazoxan also labels additional sites that do not recognize catecholamines but bind with high affinity several chemically distinct drugs previously assumed to be highly selective for alpha 2-adrenergic receptors [Mol. Pharmacol. 35:324-330 (1989...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-01-01 00:00:00
abstract::The ligand-binding sites of many G protein-coupled receptors (GPCRs) are situated around and deeply embedded within the central pocket formed by their seven transmembrane-spanning α-helical domains. Generally, these binding sites are assumed accessible to endogenous ligands from the aqueous phase. Recent advances in t...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.118.115113
更新日期:2019-11-01 00:00:00
abstract::The intermediate-conductance Ca2+-activated K+ channel (KCa3.1) constitutes an attractive pharmacological target for immunosuppression, fibroproliferative disorders, atherosclerosis, and stroke. However, there currently is no available crystal structure of this medically relevant channel that could be used for structu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.108068
更新日期:2017-04-01 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
abstract::Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of Gα protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.067454
更新日期:2011-02-01 00:00:00
abstract::The hexapeptide [pGlu6,Pro9]substance P (SP)6-11, septide, has been shown to be an agonist as potent as SP in eliciting smooth muscle contraction in several in vitro preparations, while being a poor competitor of labeled SP binding. These results, as well as other pharmacological data, have suggested the existence of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract::We demonstrate that gastrin-releasing peptide (GRP) can inhibit the proliferation of human immortal nontumorigenic (184-B5) mammary epithelial cells ectopically expressing the human GRP receptor. Growth of Balb 3T3 cells ectopically expressing relatively high levels of the GRP receptor was also inhibited by GRP; howev...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-03-01 00:00:00
abstract::NAD(P):quinone acceptor oxidoreductase (quinone reductase) (DT-diaphorase, EC 1.6.99.2) is involved in the process of reductive activation of cytotoxic antitumor quinones and nitrobenzenes. In this study, we initially examined the relative abilities of mouse, rat, and human quinone reductases to reduce two prodrugs, C...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00