Abstract:
:Capsaicin (vanilloid) sensitivity has long served as the functional signature of a subset of nociceptive sensory neurons. Mutagenesis studies have revealed seemingly distinct regions involved in mediating ligand binding and channel activation at the capsaicin binding site. Residue 547 (transmembrane region 4) mediates significant species differences in resiniferatoxin (RTX) sensitivity, and the Ser(512) residue is critical in discriminating between pH and capsaicin gating. In the present study, the pharmacological profiles of a variety of ligands were studied to investigate cross-talk between these two regions. Exchange of residue 547 between species mediated a difference in capsaicin and RTX-dependent gating. Likewise, the potency of iodoresiniferatoxin (I-RTX) and a novel transient receptor potential vanilloid 1 antagonist were also altered. Experiments using the S512Y mutant channel have confirmed the importance of residue 512 for functional interaction of capsaicin and our novel antagonist. In this study, we were surprised to find that the mutation S512Y converted the activity of the antagonist I-RTX into an intrinsic agonist, albeit with a lower potency than its parent compound, RTX. Recent studies have proposed a novel model for the receptor, based on the X-ray crystal structure of the voltage-dependent potassium channel, in which both the 512 and 547 amino acid residues are in close proximity. Our data support the model whereby intracellular ligand interaction occurs within an S3-S4 "sensor" domain, enabling binding of ligands to be transduced to functional gating of the channel. The binding pocket also seems to be exquisitely sensitive to residue-specific interaction with ligands, because subtle changes in either ligand or channel structure can have profound effects on channel activity.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Johnson DM,Garrett EM,Rutter R,Bonnert TP,Gao YD,Middleton RE,Sutton KGdoi
10.1124/mol.106.023945subject
Has Abstractpub_date
2006-09-01 00:00:00pages
1005-12issue
3eissn
0026-895Xissn
1521-0111pii
mol.106.023945journal_volume
70pub_type
杂志文章abstract::Dysregulation of the chemokine system is implicated in a number of autoimmune and inflammatory diseases, as well as cancer. Modulation of chemokine receptor function is a very promising approach for therapeutic intervention. Despite interest from academic groups and pharmaceutical companies, there are currently few ap...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.119.116954
更新日期:2019-12-01 00:00:00
abstract::When expressed via an inducible promoter in human embryonic kidney 293 cells, the rat Mas-related gene D (rMrgD) receptor responded to beta-alanine but not L-alanine by elevating intracellular [Ca(2+)], stimulating phosphorylation of the mitogenactivated protein kinases known as extracellular signal-regulated kinase (...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.018788
更新日期:2006-02-01 00:00:00
abstract::The binding of agonists and antagonists to alpha 2-adrenergic receptors of human platelets was studied. The receptors showed homogeneous affinities for antagonists but two affinity states for the agonist (-)-epinephrine, which were modulated by guanine nucleotides. Van't Hoff plots of antagonist binding had a break po...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-03-01 00:00:00
abstract::Many human cancers show constitutive or amplified expression of the transcriptional regulator and oncoprotein Myc, making Myc a potential target for therapeutic intervention. Here we report the down-regulation of Myc activity by reducing the availability of Max, the essential dimerization partner of Myc. Max is expres...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.054858
更新日期:2009-09-01 00:00:00
abstract::S-Adenosylmethionine (SAMe) and its metabolite 5'-methylthioadenosine (MTA) inhibit mitogen-induced proliferative response in liver and colon cancer cells. SAMe and MTA are also proapoptotic in liver cancer cells by selectively inducing Bcl-x(S) expression. The aims of this work were to assess whether these agents are...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.054411
更新日期:2009-07-01 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::A variety of direct and indirect techniques have revealed the existence of ATP-sensitive potassium (KATP) channels in the inner membranes of mitochondria. The molecular identity of these mitochondrial KATP (mitoKATP) channels remains unclear. We used a pharmacological approach to distinguish mitoKATP channels from cla...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-06-01 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::The fluorogenic sulfhydryl probe 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) (1-50 nM) is used to characterize the functional role and location of highly reactive thiol groups on the ryanodine-sensitive Ca2+ release channel complex [i.e., ryanodine receptors (RyRs)] of skeletal and cardiac junctional...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract::Anthracyclines are effective anticancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron and to perturb iron metabolism (Mol Pharmacol 68:261-271, 2005). These effects on iron-trafficking remain poorly understood, but they are important to decipher because trea...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.041335
更新日期:2008-03-01 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::The c-Myc (MYC) transcription factor is a major cancer driver and a well-validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. In this study, we report the ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107623
更新日期:2017-04-01 00:00:00
abstract::mRNA levels for the protooncogene c-fos, measured by Northern blot analysis, were greatly increased in brains of mice undergoing ethanol withdrawal seizures. This increase was transient (levels were increased at the time of the seizure and returned to normal by 24 hr or less after seizure) and was larger in hippocampu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-03-01 00:00:00
abstract::The recent molecular cloning of the genes encoding three somatostatin (SRIF) receptor subtypes has allowed for the individual expression of these receptors in mammalian cells and characterization of their respective pharmacological profiles. In the present study, we have investigated the affinities of a battery of SRI...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-06-01 00:00:00
abstract::alpha-Amidation is essential for the function of many peptides in intercellular communication. This C-terminal modification is mediated in a two-step process by the hydroxylase and lyase activities of the bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The first step, catalyzed by peptidylgly...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.55.6.1067
更新日期:1999-06-01 00:00:00
abstract::The induction of human inducible nitric-oxide synthase (iNOS) expression depends (among other factors) on activation of the signal transducer and activator of transcription 1 (STAT1) pathway. Therefore, the STAT1 pathway may be an appropriate target for the development of inhibitors of iNOS expression. HeLa S3 cells t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.2.383
更新日期:2003-02-01 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::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::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::Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. CYP2E1 has also been implicated in alcohol liver disease because of its contribution to oxidative stress. Previously, polymorphic alleles with mutations in i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::Nafazatrom, an antithrombotic and antimetastatic agent containing a pyrazolone functionality, is a reducing substrate for the peroxidase activity of prostaglandin H (PGH) synthase. Nafazatrom inhibits the hydroperoxide-dependent oxidation of phenylbutazone, stimulates the reduction of 15-hydroperoxy-5,8,11,13-eicosate...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-09-01 00:00:00
abstract::The effects of dimethyl sulfoxide (DMSO) on subsynaptic response and quantal release of transmitter have been studied at the mammalian neuromuscular junction. Subsynaptically, at low concentrations (up to 1% by volume), DMSO prolongs the time course of decay of miniature endplate currents, (MEPCs), with no significant...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-12-01 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::Several 2-amino-3-benzoylthiophenes were found to increase the binding of [3H]N6-cyclohexyladenosine to A1 adenosine receptors in rat brain membranes. Concentration-response curves were bell-shaped, with up to 45% stimulation of binding at 10 microM followed by inhibition at higher concentrations. Because these compou...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-12-01 00:00:00
abstract::1-Deoxynojirimycin (DNM) is a saccharide decoy that inhibits cellular alpha-glucosidase I-II activity. Treatment by DNM of human immunodeficiency virus (HIV)-infected lymphocyte cultures inhibits virus spread. The functional properties of the membrane-associated Env glycoprotein (Env) modified in the presence of DNM r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.1.186
更新日期:2002-01-01 00:00:00
abstract::Signaling by G-protein-coupled receptors is often considered a uniform process, whereby a homogeneously activated proportion of randomly distributed receptors are activated under equilibrium conditions and produce homogeneous, steady-state intracellular signals. While this may be the case in some biologic systems, the...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.115.100248
更新日期:2015-09-01 00:00:00
abstract::The availability of high-affinity agonists for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has led to significant advances in our understanding of the functional role of PPARbeta/delta. In this study, a new PPARbeta/delta antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.065508
更新日期:2010-09-01 00:00:00
abstract::Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-02-01 00:00:00
abstract::A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::Bitopic binding properties apply to a variety of muscarinic compounds that span and simultaneously bind to both the orthosteric and allosteric receptor sites. We provide evidence that fluorescent pirenzepine derivatives, with the M1 antagonist fused to the boron-dipyrromethene [Bodipy (558/568)] fluorophore via spacer...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.085670
更新日期:2013-07-01 00:00:00