Abstract：
:All five (m1-m5) muscarinic receptors are sensitive to allosteric regulation, but gallamine is considerably more potent in slowing the dissociation of N-[3H]methylscopolamine (NMS) from the m2 subtype than from the m3 or m5 subtypes. To study the structural basis for the preference of gallamine for the m2 subtype, we evaluated [3H]NMS-gallamine interactions with chimeric receptors in which segments of the m5 receptor were systematically replaced with the corresponding m2 sequence. Substitutions that included the sixth transmembrane domain and third extracellular loop resulted in marked increases in the potency of gallamine, but substitutions that did not include these regions were without effect. A similar substitution was investigated using m2/m3 chimeric receptors, in which a segment extending from the middle of the sixth transmembrane domain to the carboxyl terminus was exchanged. As with the m2/m5 constructs, substitution of the m2 carboxyl-terminal segment into the m3 subtype significantly increased the potency of gallamine. Furthermore, the converse substitution reduced the potency of gallamine dramatically, to approximately that seen for the m3 subtype itself. It appears that this portion of the receptor is a critical determinant for the binding of gallamine and/or the allosteric interactions between gallamine and [3H]NMS.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Ellis J,Seidenberg M,Brann MRsubject
Has Abstractpub_date
1993-09-01 00:00:00pages
583-8issue
3eissn
0026-895Xissn
1521-0111journal_volume
44pub_type
杂志文章abstract：:Compound BM5 [N-methyl-N(1-methyl-4-pyrrolidino-2-butynyl) acetamide] has previously been described as an agonist at postsynaptic muscarinic receptors and as an antagonist at presynaptic receptors. In the current work, we studied the ability of this compound to selectively stimulate phosphoinositide (PI) turnover in C...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-09-01 00:00:00
abstract：:Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absen...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.58.6.1247
更新日期：2000-12-01 00:00:00
abstract：:Obesity is now recognized as a rapidly increasing worldwide threat to health, largely as a result of causing diabetes. Thus, considerable efforts are underway in the pharmaceutical industry to find drugs to treat this condition. Target validation in various academic and industrial laboratories has revealed a number of...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.106.026104
更新日期：2006-09-01 00:00:00
abstract：:The present study was conducted to establish a pharmacological method of controlling growth of vascular smooth muscle cells (VSMC) by blocking calcium entry. In cultured rat VSMC, 1 nM platelet-derived growth factor (PDGF) induced a biphasic elevation of cytoplasmic free calcium concentration, ([Ca2+]c). The second su...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-10-01 00:00:00
abstract：:To screen for residues of hKv1.3 important for current block by the phenylalkylamine verapamil, the inactivated-state-reduced H399T mutant was used as a background for mutagenesis studies. This approach was applied mainly to abolish the accumulation in the inactivated blocked state, recovery from which in the wild typ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.012401
更新日期：2005-10-01 00:00:00
abstract：:The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.118.113480
更新日期：2019-01-01 00:00:00
abstract：:The effects of the insulin-releasing sulfonylurea tolbutamide on the cytoplasmic Ca2+ concentration [( Ca2+]i) in individual pancreatic beta-cells or suspensions of beta-cells were analyzed using the probe fura-2 and dual-wavelength fluorometry. Subsequent additions of 1, 10, and 100 microM tolbutamide induced a grade...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-03-01 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：:Adenosine receptors of the A1 and A2 subtypes were characterized in membranes from DDT1 MF-2 smooth muscle cells. These cells possess a high density of A1 adenosine receptors (Bmax = 0.8-0.9 pmol/mg of protein), as measured by both agonist and antagonist radioligands. Agonists compete for [125I]N6-[2-(4-amino-3-iodoph...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-02-01 00:00:00
abstract：:Variant neuroblastoma cell clones were selected for resistance to the cytotoxic effects of neurotoxins that cause persistent activation of sodium channels. Three classes of variant clones were obtained: sodium channel-deficient clones, which have markedly reduced numbers of functional sodium channels; scorpion toxin-r...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1982-07-01 00:00:00
abstract：:Ribavirin used in therapies against hepatitis C virus (HCV) is potentially efficient against other viruses but presents a high cytotoxicity. Several ribavirin triphosphate analogs modified on the ribose moiety were synthesized and tested in vitro on the RNA polymerases of HCV, phage T7, and HIV-1 reverse transcriptase...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.63.3.538
更新日期：2003-03-01 00:00:00
abstract：:In vivo administration of the porphyrogenic agent allylisopropylacetamide (AIA) to phenobarbital-pretreated rats results in marked loss of hepatic cytochrome P-450 content. Using isozyme-selective functional markers, we now show that such loss reflects inactivation of several phenobarbital-inducible and constitutive i...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-08-01 00:00:00
abstract：:As a member of the transient receptor potential (TRP) ion channel superfamily, the ligand-gated ion channel TRPA1 has been implicated in nociceptive function and pain states. The endogenous ligands that activate TRPA1 remain unknown. However, various agonists have been identified, including environmental irritants (e....
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.033621
更新日期：2007-05-01 00:00:00
abstract：:Extracellular ATP activates two distinct types of P2 purinoreceptor-mediated signaling pathways in macrophages, 1) the rapid formation of nonselective pores/channels in the plasma membrane and 2) a guanine nucleotide-binding protein-dependent stimulation of phosphotidylinositol-specific phospholipase C, with subsequen...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-07-01 00:00:00
abstract：:The NO/cGMP signaling pathway plays a major role in the cardiovascular system, in which it is involved in the regulation of smooth muscle tone and inhibition of platelet aggregation. Under pathophysiological conditions such as endothelial dysfunction, coronary artery disease, and airway hyperreactivity, smooth muscle ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.020909
更新日期：2006-06-01 00:00:00
abstract：:Pyrethroid insecticides are synthetic neurotoxins patterned after the naturally occurring pyrethrins. Their mechanism of action is thought to involve effects primarily at the voltage-sensitive sodium channel of both insect and mammalian neurons, although recent studies have raised the possibility that these compounds ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1988-07-01 00:00:00
abstract：:Ceramides are naturally occurring compounds recognized to mediate apoptosis. N-acylsphingosines, containing a double bond at carbons 4 and 5 of their sphingoid backbone, are thought to be the active form, because N-acylsphinganines with completely saturated sphingoid are inactive. In the present study, we synthesized ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.5.1249
更新日期：2001-05-01 00:00:00
abstract：:Inhibitors of the proteasome, a multicatalytic proteinase complex responsible for intracellular proteolysis, activate programmed cell death in part through the c-Jun-N-terminal kinase (JNK). Proteasome inhibitors also induce mitogen-activated protein kinase phosphatase-1 (MKP-1), however, which can inactivate JNK, and...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.003400
更新日期：2004-12-01 00:00:00
abstract：:The competitive antagonist alpha-conotoxin-MII (alpha-CTx-MII) is highly selective for the alpha3beta2 neuronal nicotinic receptor. Other receptor subunit combinations (alpha2beta2, alpha4beta2, alpha3beta4) are >200-fold less sensitive to blockade by this toxin. Using chimeric and mutant subunits, we identified amino...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.51.2.336
更新日期：1997-02-01 00:00:00
abstract：:Recombinant rat D3 dopamine receptors heterologously expressed in Chinese hamster ovary (CHO) cells are functionally coupled to endogenous G proteins. The affinity of the receptors for agonists is regulated by guanine nucleotides in the same manner as that of other G protein-linked receptors. The magnitude of the chan...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-01-01 00:00:00
abstract：:4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz), a prototype drug candidate containing a 1,2-dithiole-3-thione moiety, has been widely studied as a cancer chemopreventive agent. Oltipraz and other novel 1,2-dithiole-3-thione congeners have the capability to prevent insulin resistance via AMP-activated protei...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.051128
更新日期：2009-01-01 00:00:00
abstract：:The gamma-aminobutyric acid (GABA) receptor type B (GABA(B)R) is constituted of at least two homologous proteins, GABA(B)R1 and GABA(B)R2. These proteins share sequence and structural similarity with metabotropic glutamate and Ca(2+)-sensing receptors, both of which are sensitive to Ca(2+). Using rat brain membranes, ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.57.3.419
更新日期：2000-03-01 00:00:00
abstract：:Pancreatic cancer is one of the most lethal types of tumors with no effective therapy available; is currently the third leading cause of cancer in developed countries; and is predicted to become the second deadliest cancer in the United States by 2030. Due to the marginal benefits of current standard chemotherapy, the...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.118.115444
更新日期：2019-07-01 00:00:00
abstract：:Merbarone (5-[N-phenyl carboxamido]-2-thiobarbituric acid) is an anticancer drug that inhibits the catalytic activity of DNA topoisomerase II (topo II) without damaging DNA or stabilizing DNA-topo II cleavable complexes. Although the cytotoxicity of the complex-stabilizing DNA-topo II inhibitors such as VP-16 (etoposi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-03-01 00:00:00
abstract：:Tumor necrosis factor α (TNFα) plays a vital role in cancer progression as it is associated with inflammation and promotion of cancer angiogenesis and metastasis. The effects of TNFα are mediated by its downstream target, the oncogene lysine-rich CEACAM1 coisolated protein (LYRIC, also known as metadherin or astrocyte...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.107870
更新日期：2017-05-01 00:00:00
abstract：:Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
abstract：:Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels encoded by the Slo1 gene are ubiquitously expressed, and they play a role in regulation of many cell types. In excitable cells, BK(Ca) channels and voltage-activated Ca(2+) channels often form functional complexes that allow the cytoplasmic domains of BK(Ca) ch...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.040733
更新日期：2008-02-01 00:00:00
abstract：:We reported previously that protein associated with Myc (PAM) interacts with the C2 domain of type V adenylyl cyclase (ACV-C2) and that purified PAM is a potent inhibitor of Galphas-stimulated ACV activity (J Biol Chem 276:47583-47589, 2001). The present study was conducted to identify the region in PAM that inhibits ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.005355
更新日期：2005-01-01 00:00:00
abstract：:Cytosolic sulfotransferase 1C3 (SULT1C3) is the least characterized of the three human SULT1C subfamily members. Originally identified as an orphan SULT by computational analysis of the human genome, we recently reported that SULT1C3 is expressed in human intestine and LS180 colorectal adenocarcinoma cells and is upre...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.106005
更新日期：2016-11-01 00:00:00
abstract：:The effects of ethanol on a number of electrophysiological parameters were examined in 10 different voltage-gated potassium channels expressed in Xenopus oocytes. None of the channels examined was highly sensitive to ethanol, but there was significant variability among the channels tested at concentrations of ethanol ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-09-01 00:00:00
