Abstract:
:The firmest candidate among the transmembrane portions of the nicotinic acetylcholine receptor (AChR) to be in contact with the lipid bilayer is the fourth segment, M4. To explore the contribution of alphaM4 amino acid residues of mouse AChR to channel gating, we combined site-directed mutagenesis with single-channel recordings. Two residues in alphaM4, Cys418 and Thr422, were found to significantly affect gating kinetics when replaced by alanine. AChRs containing alphaC418A and alphaT422A subunits form channels characterized by a 3- and 5-fold reduction in the mean open time, respectively, suggesting an increase in the closing rate due to the mutations. The calculated changes in the energy barrier for the channel closing process show unequal and coupled contributions of both positions to channel gating. Single-channel recordings of hybrid wild-type alpha/alphaT422A AChR show that the closing rate depends on the number of alpha subunits mutated. Each substitution of threonine to alanine changes the energy barrier of the closing process by approximately 0.5 kcal/mol. Recordings of channels activated by high agonist concentration suggest that these mutations also impair channel opening. Both Cys418 and Thr422 have been postulated to be in contact with the lipid milieu and are highly conserved among species and subunits. Our results support the involvement of lipid-exposed residues in alphaM4 in AChR channel gating mechanism.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Bouzat C,Roccamo AM,Garbus I,Barrantes FJdoi
10.1124/mol.54.1.146subject
Has Abstractpub_date
1998-07-01 00:00:00pages
146-53issue
1eissn
0026-895Xissn
1521-0111journal_volume
54pub_type
杂志文章abstract::In previous studies, it was shown that the overexpression of beta2-adrenoceptor (beta2AR) in the hearts of transgenic mice (Tg) leads to agonist-independent activation of adenylate cyclase and enhanced myocardial function. Here, we measured the physical coupling of beta2AR and Gs by evaluating the coimmunoprecipitatio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.2.187
更新日期:1997-08-01 00:00:00
abstract::The chemokine receptor CCR2 is a G protein-coupled receptor that is activated primarily by the endogenous CC chemokine ligand 2 (CCL2). Many different small-molecule antagonists have been developed to inhibit this receptor, as it is involved in a variety of diseases characterized by chronic inflammation. Unfortunately...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.086850
更新日期:2013-10-01 00:00:00
abstract::We describe the receptor binding and antagonistic properties of two novel nonpeptide antagonists, FR167344 (3-bromo-8-[2,6-dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamido acetyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride) and FR173657 (8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylg...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.2.171
更新日期:1997-02-01 00:00:00
abstract::Fusion proteins were generated between the human 5-hydroxytryptamine (5-HT)(1A) receptor and both wild-type (Cys(351)) and pertussis toxin-resistant (Gly(351) and Ile(351)) forms of G(i1). These were expressed stably. Pertussis toxin treatment substantially reduced basal high-affinity GTPase activity in clones express...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-10-01 00:00:00
abstract::Receptors from distant species may have conserved functions despite significant differences in protein sequences. Whereas the noncritical residues are often changed in distant species, the amino acids critical in receptor functions are often conserved. Studying the conserved residues between receptors from distant spe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.074500
更新日期:2011-11-01 00:00:00
abstract::Microglia, as phagocytes and antigen-presenting cells in the central nervous system, are activated in such disease processes as stroke and multiple sclerosis. Because peripheral macrophages are capable of producing endocannabinoids, we have examined endocannabinoid production in a macrophage-colony stimulating factor ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.4.999
更新日期:2004-04-01 00:00:00
abstract::CC and CXC chemokines coinduced in fibroblasts and leukocytes by cytokines and microbial agents determine the number of phagocytes infiltrating into inflamed tissues. Interleukin-8/CXCL8 and stromal cell-derived factor-1/CXCL12 significantly and dose-dependently increased the migration of monocytes, expressing the cor...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.045146
更新日期:2008-08-01 00:00:00
abstract::The epithelial sodium channel (ENaC) is believed to represent the rate-limiting step for sodium absorption in the renal collecting duct. Consequently, ENaC is a central effector affecting systemic blood volume and pressure. Sodium and water transport are dysregulated in diabetes mellitus. Peroxisome proliferator-activ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.056911
更新日期:2009-12-01 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 liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocyte...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.002410
更新日期:2005-01-01 00:00:00
abstract::2',3'-Dideoxyadenosine (ddAdo) and its deamination product 2',3'-dideoxyinosine (ddIno) (didanosine) inhibit the replication and infectivity of the human immunodeficiency virus (HIV) in a number of in vitro assay systems. Early clinical studies (phase I) have indicated a role for ddIno in the treatment of patients wit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-07-01 00:00:00
abstract::The aryl hydrocarbon receptor (AHR) and its DNA binding partner, the AHR nuclear translocator (ARNT), are basic helix-loop-helix transcription factors that mediate many of the toxic and carcinogenic effects of polyhalogenated aromatic hydrocarbons. The basic regions of the AHR and ARNT contact the GCGTG recognition si...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-10-01 00:00:00
abstract::In mammals, receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are divided into three pharmacological classes, which are denoted GABAA, GABAB, and GABAC. GABAC receptors are defined by their insensitivity to the GABAA receptor antagonist bicuculline and the GABAB receptor agonist (-)-baclofen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-10-01 00:00:00
abstract::Hepatic CYP2E1 is induced in several models of alcohol administration, but clinically relevant pathology is only observed in rats in a model involving the continuous intragastric administration of an ethanol-containing, corn oil-based, high-fat diet. The level of CYP2E1 correlates with the degree of liver pathology in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.6.944
更新日期:1997-06-01 00:00:00
abstract::Analysis of the distribution of mRNA encoding the serotonin (5-hydroxytryptamine) 5-HT(2A) receptor and the mu opioid peptide receptor in rat brain demonstrated their coexpression in neurons in several distinct regions. These regions included the periaqueductal gray, an area that plays an important role in morphine-in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.048272
更新日期:2008-11-01 00:00:00
abstract::The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we h...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107326
更新日期:2017-03-01 00:00:00
abstract::Glutathione-liganded binuclear dinitrosyl iron complex (glut-BDNIC) has been proposed to be a donor of nitric oxide (NO). This study was undertaken to investigate the mechanisms of vasoactivity, systemic hemodynamic effects, and pharmacokinetics of glut-BDNIC. To test the hypothesis that glut-BDNICs vasodilate by rele...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.117.110957
更新日期:2018-05-01 00:00:00
abstract::An alteration in the balance between a T-helper type 2 cell (Th2) response and a Th1 response may predispose to the development of bronchial asthma. Interleukin-18 (IL-18) has an ability to promote both Th1 and Th2 responses, depending on the surrounding cytokine environment. Reactive oxygen species (ROS) play a cruci...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.024737
更新日期:2006-10-01 00:00:00
abstract::Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepression. However, effective...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.006254
更新日期:2005-03-01 00:00:00
abstract::The aptamer mechanism of action involves the direct interaction of oligonucleotide with protein and is responsible for the biological effects of many pharmacologically active oligodeoxynucleotides. In the work reported here, we have determined the effects of aptamers on the secondary, tertiary, and quaternary structur...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-05-01 00:00:00
abstract::The anticancer agent 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-Me) typically induce a broad spectrum of growth-inhibitory, proapoptotic, and antiangiogenic responses. Treatment of Panc1, Panc28, and L3.6pL pancreatic cancer cells with low micromolar concentrations of CDDO or CDDO-...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.064451
更新日期:2010-08-01 00:00:00
abstract::The effects of saturating concentrations of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] and the pyrethroid insecticides cismethrin and deltamethrin on alkaloid-dependent activation of the voltage-sensitive sodium channel were studied using measurements of 22Na+ uptake into mouse brain synaptosomes. In survey e...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-05-01 00:00:00
abstract::We describe here the cloning and characterization of a rat homolog of the chemokine receptor CXCR3. The predicted amino acid sequence of rat CXCR3 contains 367 amino acid residues, sharing 96 and 87% amino acid sequence identity to the murine and human CXCR3, respectively. Among a large panel of chemokines tested, onl...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2000-06-01 00:00:00
abstract::Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.118.113118
更新日期:2019-01-01 00:00:00
abstract::We examined the block of N-methyl-D-aspartate (NMDA) receptors by n-alkyl (straight chain) diamines and related monoamines and triamines using whole-cell voltage clamp recording of NMDA receptor currents in cultured rat hippocampal neurons and [3H] dizocilpine binding to rat forebrain homogenates. At -60 mV, the diami...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-01-01 00:00:00
abstract::Histone deacetylase inhibitors (HDACi), which have emerged as a new class of anticancer agents, act by modulating expression of genes controlling apoptosis or cell proliferation. Here, we compared the effect of HDACi on transcriptional activation by estrogen or glucocorticoid receptors (ER and GR, respectively), two m...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.014514
更新日期:2005-12-01 00:00:00
abstract::Up-regulation of fractalkine is involved in vascular and tissue damage in inflammatory conditions. Resveratrol has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Its regulatory effects on expression of fractalkine in vascular endothelial cells and fractalkine receptor CX3CR1 in monocytes ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.022392
更新日期:2006-07-01 00:00:00
abstract::Mammalian A2-adenosine receptor binding subunits (A2AR) can be visualized by covalent labeling with the photoaffinity crosslinking ligand 125I-2-[4-[2-[2-[(4-aminophenyl)methylcarbonylamino] ethylaminocarbonyl]ethyl]phenyl]ethylamino-5'-N-ethylcarboxamidoad enosine or directly with the azide derivative described in th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-08-01 00:00:00
abstract::To understand the molecular mechanism by which the angiotensin II (AII) type 1 receptor (AT1 receptor) transduces its biological signal, we examined the role of various signaling molecules involved in AT1 receptor signaling in Chinese hamster ovary cells stably transfected with the AT1 receptor. AT1 receptor-transfect...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::It is established that agmatine, an endogenously formed decarboxylated arginine, is a weak competitive inhibitor of neuronal nitric-oxide synthase (nNOS) with an apparent Ki value of 660 microM [Biochem J 316:247-249, 1996]. Although agmatine is known to bind to alpha-adrenergic and imidazoline receptors, it has been ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.1.24
更新日期:2001-01-01 00:00:00