Abstract:
:Phosphorylation of tau protein promotes stability of the axonal cytoskeleton; aberrant tau phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases and phosphatases that modulate tau phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect tau dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, tau protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 microM) and FK-520 (5 microM); these preparations showed enhanced tau phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on tau protein, namely, Thr181 and Thr231, is regulated by calcineurin.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Garver TD,Kincaid RL,Conn RA,Billingsley MLkeywords:
subject
Has Abstractpub_date
1999-04-01 00:00:00pages
632-41issue
4eissn
0026-895Xissn
1521-0111journal_volume
55pub_type
杂志文章abstract::Dietary lipids and fat-soluble micronutrients are solubilized in mixed micelles and absorbed in the small intestine. Based on an assumption that cholesterol and other fat-soluble molecules share a number of transport mechanisms and the fact that Niemann-Pick C1-like 1 (NPC1L1) is critical for intestinal cholesterol ab...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.043034
更新日期:2008-07-01 00:00:00
abstract::The binding affinities of 16 7-substituted 2,3-dichlorodibenzo-p-dioxins for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cytosolic receptor protein from male Wistar rats have been determined. The EC50 value for each compound was estimated by competitive displacement of [3H]TCDD and the data illustrated that the dif...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-06-01 00:00:00
abstract::Accumulated evidence suggests that dopamine and dopamine D1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought to be linked to adenylyl cyclase, has...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.1.6
更新日期:1997-01-01 00:00:00
abstract::The cannabinoid analog abnormal cannabidiol [abn-cbd; (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB(1) or CB(2) receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive, and is i...
journal_title:Molecular pharmacology
pub_type: 评论,杂志文章
doi:10.1124/mol.63.3.699
更新日期:2003-03-01 00:00:00
abstract::In previous studies, we have shown that mouse RAW 264.7 macrophages possess pyrimidinoceptors, coupled to a phosphoinositide-specific phospholipase C, with a higher specificity for UTP than for ATP. In the current study, we explored the mechanism involved in the UTP-induced intracellular acidification seen in this cel...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.2.313
更新日期:1998-02-01 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::The effect of the neuromuscular blocker alcuronium on the binding of N-[3H]-methylscopolamine [( 3H]NMS) and l-[3H]quinuclidinylbenzilate ([3H]QNB) to muscarinic binding sites in rat heart atria, longitudinal smooth muscle of the ileum, cerebral cortex, cerebellum, and submaxillary glands was measured using filtration...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-11-01 00:00:00
abstract::The human histamine H(4)-receptor (hH(4)R) possesses high constitutive activity and, like the human H(1)-receptor (hH(1)R), is involved in the pathogenesis of type-I allergic reactions. The study aims were to explore the value of dual H(1)/H(4)R antagonists as antiallergy drugs and to address the question of whether H...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.058651
更新日期:2009-11-01 00:00:00
abstract::Voltage-gated sodium channels are inhibited by many local anesthetics, antiarrhythmics, and antiepileptic drugs. The local anesthetic lidocaine appears to be able to access its binding site in the sodium channel only from the membrane phase or from the internal face of the channel. In contrast, the antiepileptic drug ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.090472
更新日期:2014-02-01 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::We have cloned new 5-Hydroxytryptamine 4 (5-HT4) receptor splice variants from mouse (m5-HT4(e)R and m5-HT4(f)R), rat (r5-HT4(e)R), and human brain tissue (h5-HT4(e)R) which differ, as do the previously described 5-HT4 receptor variants, in the length and composition of their intracellular C termini after the common s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-05-01 00:00:00
abstract::Because cytotoxicity by an alkylating agent such as N-methyl-N'-nitrosoguanidine is markedly increased in adenine methylase-deficient dam-3 Escherichia coli, it was of interest to assess whether mismatch repair was similarly important in the repair of DNA damage induced by cis-diamminedichloroplatinum(II) (CDDP). The ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-07-01 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::A high cytoplasmic Na(+) concentration may contribute to N-methyl-D-aspartate (NMDA)-induced excitotoxicity by promoting Ca(2+) influx via reverse operation of the Na(+)/Ca(2+) exchanger (NaCaX), but may simultaneously decrease the electrochemical Ca(2+) driving force by depolarizing the plasma membrane (PM). Digital ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.56.3.619
更新日期:1999-09-01 00:00:00
abstract::Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M(1) muscarinic receptor agonist from a novel st...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.6.1297
更新日期:2002-06-01 00:00:00
abstract::Human and bovine dopamine transporters (DAT) demonstrate discrete functional differences in dopamine (DA), 1-methyl-4-phenylpyridium (MPP(+)) transport, and cocaine analog binding. In a previous study, the functional analyses on the chimeras of human and bovine DAT have revealed that the region from residues 133 throu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2000-05-01 00:00:00
abstract::The effects of tournefolic acid B (TAB) and two ester derivatives, TAB methyl ester (TABM) and TAB ethyl ester (TABE), on N-methyl-D-aspartate (NMDA)-mediated excitotoxicity and the underlying mechanisms were investigated. Treatment with 50 microM NMDA elicited neuronal death by 48.7 +/- 5.1%, coinciding with the appe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.018770
更新日期:2006-03-01 00:00:00
abstract::The D2 dopamine receptor (D2R) was examined for its ability to mediate nuclear factor-kappaB (NF-kappaB) activation through G proteins. Stimulation of D2R-transfected HeLa cells with its agonist quinpirole induced the expression of a NF-kappaB luciferase reporter and formation of NF-kappaB-DNA complex. This response w...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.2.447
更新日期:2003-08-01 00:00:00
abstract::The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the α7 subunit are unique because of their high Ca(2+) permeability and fast desensitization. nAChR agonists elicit a t...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.116.104240
更新日期:2016-09-01 00:00:00
abstract::Retinoid X receptor α [RXRα; nuclear receptor (NR)2B1] is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathologic conditions. During inflammation, RXRα undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, wh...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.085555
更新日期:2013-08-01 00:00:00
abstract::Inflammation contributes to pain hypersensitivity through multiple mechanisms. Among the most well characterized of these is the sensitization of primary nociceptive neurons by arachidonic acid metabolites such as prostaglandins through G protein-coupled receptors. However, in light of the recent discovery that the no...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.040832
更新日期:2008-02-01 00:00:00
abstract::Extracellular protons inhibit N-methyl-D-aspartate (NMDA) receptors with an IC50 value in the physiological pH range. To identify the molecular determinants of proton sensitivity, we used scanning mutagenesis of the NR1 subunit to search for residues that control proton inhibition of NMDA receptors. Homology modeling ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.6.1212
更新日期:2003-06-01 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::The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.042663
更新日期:2008-04-01 00:00:00
abstract::The mouse 5-hydroxytryptamine4a (5-HT4a) receptor is an unusual member of the G protein-coupled receptor superfamily because it possesses two separate carboxyl-terminal palmitoylation sites, which may allow the receptor to adopt different conformations in an agonist-dependent manner (J Biol Chem 277:2534-2546, 2002). ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008748
更新日期:2005-05-01 00:00:00
abstract::A method was developed to measure the formation of glutathione adducts of 1-chloro-2,4-dinitrobenzene (CDNB) and 2,4-dichloro-1-nitrobenzene (DCNB) in periportal and pericentral regions of the liver lobule in the isolated perfused rat liver by surface reflectance spectrophotometry. Conjugates of DCNB and CDNB are rele...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-01-01 00:00:00
abstract::This study describes experiments investigating the mechanism of activation of A1 adenosine receptors. Isolated rat fat cells were used as a cellular model. The A1 receptors of these cells were covalently labeled with the agonist photoaffinity label R-2-azido-N6-p-hydroxyphenylisopropyladenosine. The covalent incorpora...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::Studies were carried out to elucidate the mechanism whereby thyroid hormone (T3) induces NADPH:cytochrome P450 oxidoreductase (P450R) mRNA in rat liver in vivo. Northern blot analysis revealed that T3 treatment increases unspliced liver nuclear P450R RNA 4-fold within 8 h and that this induction precedes the induction...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.5.987
更新日期:2001-05-01 00:00:00
abstract::Norcocaine nitroxide and N-hydroxynorcocaine were found to stimulate hepatic microsomal lipid peroxidation in vitro, as measured by spin-trapping techniques using the spin trap alpha-[4-pyridyl-1-oxide]-N-tert-butylnitrone. It was determined that either norcocaine nitroxide or N-hydroxynorcocaine markedly enhanced the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-11-01 00:00:00
abstract::The effect of endocytosis inhibitors on 5-hydroxytryptamine(2A) (5-HT(2A)) receptor desensitization and resensitization was examined in transiently transfected human embryonic kidney (HEK) 293 cells and in C6 glioma cells that endogenously express 5-HT(2A) receptors. In HEK-293 cells, 5-HT(2A) receptor desensitization...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.5.1020
更新日期:2001-11-01 00:00:00