Abstract：
:Inhibition of cathepsin C, a dipeptidyl peptidase that activates many serine proteases, represents an attractive therapeutic strategy for inflammatory diseases with a high neutrophil burden. We recently showed the feasibility of blocking the activation of neutrophil elastase, cathepsin G, and proteinase-3 with a single cathepsin C selective inhibitor in cultured cells. Here we measured the fractional inhibition of cathepsin C that is required for blockade of downstream serine protease processing, in cell-based assays and in vivo. Using a radiolabeled active site probe and U937 cells, a 50% reduction of cathepsin G processing required approximately 50% of cathepsin C active sites to be occupied by an inhibitor. In EcoM-G cells, inhibition of 50% of neutrophil elastase activity required approximately 80% occupancy. Both of these serine proteases were fully inhibited at full cathepsin C active site occupancy, whereas granzyme B processing in TALL-104 cells was partially inhibited, despite complete occupancy. In vivo, leukocytes from cathepsin C(+/-) mice exhibited comparable levels of neutrophil elastase activity to wild-type animals, even though their cathepsin C activity was reduced by half. The long-term administration of a cathepsin C inhibitor to rats, at doses that resulted in the nearly complete blockade of cathepsin C active sites in bone marrow, caused significant reductions of neutrophil elastase, cathepsin G and proteinase-3 activities. Our results demonstrate that the inhibition of cathepsin C leads to a decrease of activity of multiple serine proteases involved in inflammation but also suggest that high fractional inhibition is necessary to reach therapeutically significant effects.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Méthot N,Guay D,Rubin J,Ethier D,Ortega K,Wong S,Normandin D,Beaulieu C,Reddy TJ,Riendeau D,Percival MDdoi
10.1124/mol.108.045682subject
Has Abstractpub_date
2008-06-01 00:00:00pages
1857-65issue
6eissn
0026-895Xissn
1521-0111pii
mol.108.045682journal_volume
73pub_type
杂志文章abstract：:Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of in...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.030601
更新日期：2007-03-01 00:00:00
abstract：:The Integrated Stress Response (ISR) is a signaling program that enables cellular adaptation to stressful conditions like hypoxia and nutrient deprivation in the tumor microenvironment. An important effector of the ISR is activating transcription factor 4 (ATF4), a transcription factor that regulates genes involved in...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.081810
更新日期：2013-03-01 00:00:00
abstract：:Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of del...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.64.1.51
更新日期：2003-07-01 00:00:00
abstract：:Stimulation of beta2-adrenoceptors with the selective beta2 agonist procaterol caused a biphasic decrease in cell surface M2 muscarinic receptor number in human embryonic lung 299 cells when measured with the hydrophilic antagonist [3H]N-methylscopolamine. In contrast, total muscarinic receptor number, measured with t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-04-01 00:00:00
abstract：:Ubiquitination of the human kappa opioid receptor (hKOR) expressed in Chinese hamster ovary (CHO) cells was observed in the presence of the proteasomal inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) and enhanced by the agonists (-)(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidiny) cyclohexyl] benzeneaceta...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.042846
更新日期：2008-04-01 00:00:00
abstract：:A human recombinant L-type Ca2+ channel (alpha1C,77) was coexpressed with the rat angiotensin AT1A receptor in Xenopus laevis oocytes. In oocytes expressing only alpha1C,77 channels, application of human angiotensin II (1-10 microM) did not affect the amplitude or kinetics of Ba2+ currents (IBa). In sharp contrast, in...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.54.6.1106
更新日期：1998-12-01 00:00:00
abstract：:Heart cells in culture need no external stimulation to contract; they beat rhythmically at a rate and intensity dependent on culture conditions. These cells respond to the general anesthetic 2-bromo-2-chloro-1,1,1-trifluorethane (halothane), with a loss of beating intensity and a lessening of beating rate. Increased c...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-03-01 00:00:00
abstract：:The peripheral cannabinoid receptor (CB2) is a G protein-coupled receptor that is both positively and negatively coupled to the mitogen-activated protein kinase (MAPK) and cAMP pathways, respectively, through a Bordetella pertussis toxin-sensitive G protein. CB2 receptor-transfected Chinese hamster ovary cells exhibit...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-03-01 00:00:00
abstract：:[3H]Dihydroalprenolol ([3H]DHA) has been used extensively in receptor binding studies to measure beta-adrenergic receptors in the central nervous system. Usually, nonspecific binding has been defined by high concentrations of the beta-adrenergic receptor agonist isoproterenol or antagonists such as alprenolol or propr...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-07-01 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：:Carbachol is 100 times more potent for inhibiting cyclic AMP formation than for stimulating phosphoinositide (PI) hydrolysis in chick heart cells. To determine whether this reflects differences in agonist affinity of the receptor(s) coupled to the two responses, we measured these functional responses following removal...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-12-01 00:00:00
abstract：:The functional significance of the conserved amino acids within transmembrane regions II and VII of the human 5-hydroxytryptamine (5-HT)1A receptor was analyzed by oligonucleotide-directed mutagenesis followed by transient expression of the mutated receptor genes in COS-1 cells. The substitution of a conserved asparag...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-04-01 00:00:00
abstract：:It has been suggested that elevated cytosolic free calcium plays a key role in acetaminophen-induced cell death. The present study has examined the effect of a toxic concentration of acetaminophen on cytosolic free calcium in single mouse hepatocytes, using the dye fura-2 and video imaging fluorescence microscopy. Cyt...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-04-01 00:00:00
abstract：:Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment of human immunodeficiency virus-1 (HIV-1) infection. Previous in vitro experiments have shown that HIV-1 recombinant viruses ex...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.54.2.291
更新日期：1998-08-01 00:00:00
abstract：:The incorporation of leucine into protein was studied in Ca2+-depleted and Ca2+-restored preparations of normal liver cells isolated from fed, adult male rats. Ca2+-restored cells incorporated amino acid 5-10-fold more rapidly than did Ca2+-depleted cells for incubation periods up to 1 hr. Readdition of Ca2+ at suprap...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-01-01 00:00:00
abstract：:The expression and molecular regulation of the cytochrome P450IA (P450IA) gene subfamily have been examined in rat hepatic tissue after treatment with pyridine. The microsomal ethoxyresorufin O-deethylase activity, which has been shown to be specific for the P450IA subfamily, was increased approximately 2- and 3.5-fol...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-07-01 00:00:00
abstract：:The alpha2-adrenergic receptors (alpha2-ARs) mediate signals to intracellular second messengers via guanine nucleotide binding proteins. Three human genes encoding alpha2-AR subtypes (alpha2A, alpha2B, alpha2C) have been cloned. Several chemical compounds display subtype differences in their binding and/or functional ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.53.3.370
更新日期：1998-03-01 00:00:00
abstract：:High-affinity glycine transport in neurons and glial cells is a primary means of inactivating synaptic glycine. We have synthesized a potent selective inhibitor of glycine transporter 1 (GlyT1), and characterized its activity using a quail fibroblast cell line (QT6). The glycine transporters GlyT1A, GlyT1B, GlyT1C, an...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.60.6.1414
更新日期：2001-12-01 00:00:00
abstract：:Bovine pulmonary artery endothelial (CPAE) cells respond to bradykinin, and it has been suggested that the receptors on these cells do not fall into the normal B1/B2 classification of bradykinin receptors [J. Pharmacol. Exp. Ther. 244:646-649 (1988)]. The present study describes a detailed characterization of the subt...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-03-01 00:00:00
abstract：:High expression of the aflatoxin B1 (AFB1)-8,9-epoxide-conjugating glutathione S-transferase A3 (mGSTA3) subunit in mouse liver confers intrinsic resistance to AFB1 hepatocarcinogenesis. It is not known how the gene encoding this protein is regulated. The murine mGSTA3 gene has been identified using bioinformatics. It...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.64.5.1018
更新日期：2003-11-01 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：:The use of classic antipsychotic drugs is limited by the occurrence of extrapyramidal motor symptoms, which are caused by dopamine (DA) receptor blockade in the neostriatum. We examined the impact of early-life stress on haloperidol-induced catalepsy using the rat model of prenatal restraint stress (PRS). Adult "PRS r...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.113.085530
更新日期：2013-08-01 00:00:00
abstract：:The structure-activity relationships for vasoactive intestinal peptide (VIP) receptor binding were studied using N-terminally modified VIP analogs. VIP fragments, and VIP receptor antagonists. Tissue sources included bovine coronary artery, rat mesenteric artery, rat pituitary, rat brain synaptosomes, and rat liver. E...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-06-01 00:00:00
abstract：:The cytolytic ionotropic ATP receptor P2X7 has several important roles in immune cell regulation, such as cytokine release, apoptosis, and microbial killing. Although P2X7 receptors are frequently coexpressed with another subtype of P2X receptor, P2X4, they are believed not to form heteromeric assemblies but to functi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.035980
更新日期：2007-12-01 00:00:00
abstract：:In GH3 pituitary cell homogenates, acetylcholine (ACh) (IC50 200 nM) inhibits adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity in a concentration- and GTP-dependent manner. Maximal inhibition was obtained with 10 microM ACh and corresponded to approximately a 50% decrease in basal enzyme ac...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-09-01 00:00:00
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; ho...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-04-01 00:00:00
abstract：:GABAA receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on alphabetagamma isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of alphab...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.002543
更新日期：2004-10-01 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：:The chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) shows potent and selective anticancer and antimetastatic activity. However, the mechanism by which it is initially transported into cells to induce cytotoxicity is unknown. Hence, the current investigation examined the cellular uptake of ¹⁴C-Dp4...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.113.088393
更新日期：2013-12-01 00:00:00
abstract：:15-Deoxy delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the ma...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.009449
更新日期：2005-07-01 00:00:00
