Abstract:
:Homopentameric complexes of either the A or As subunit of the 5-hydroxytryptamine3 receptor form Ca(2+)-permeable channels that can be activated by the selective agonist 1-(m-chlorophenyl)-biguanide (mCPBG). In both N1E-115 neuroblastoma cells and human embryonic kidney 293 cells stably expressing the 5-HT3 receptor As subunit, (+)-verapamil, (-)-verapamil, diltiazem, and nimodipine caused reversible and concentration-dependent (IC50 = 2.5-6.5 microM) inhibition of the increases in cytosolic [Ca2+] evoked by mCPBG. In voltage-clamped human embryonic kidney 293 cells stably expressing the 5-HT3 receptor As subunit, similar concentrations of the Ca2+ channel antagonists (IC50 = 3.0-6.8 microM) accelerated the rate at which 5-HT-evoked currents decayed without affecting the amplitude of the peak current. In equilibrium competition binding assays to membranes from Sf9 cells infected with the 5-HT3 receptor As subunit, [3H]mCPBG and [3H]granisetron were displaced by (+)-verapamil, (-)-verapamil, and diltiazem; (+)-verapamil was approximately 10-fold more potent than (-)-verapamil and approximately-30-fold more potent than diltiazem. Nimodipine neither displaced [3H]granisetron binding nor affected its displacement by diltiazem and (+)-verapamil. The stereoselectivity of verapamil binding, which contrasts with the similar potency of each isomer in functional assays, was maintained when the incubations were performed at 20 degrees or when an antagonist of the 5-HT3 receptor, [3H]granisetron, was used as the radioligand. The interaction between verapamil and either [3H]mCPBG or [3H]granisetron binding was not competitive. We conclude that the inhibition of [3H]mCPBG binding by diltiazem and verapamil is mediated by a site that is distinct from both the agonist-binding site and from the site through which nimodipine inhibits 5-HT3 receptor function. Our results provide evidence for allosteric regulation of agonist binding to 5-HT3 receptors and the first example of a ligandgated ion channel whose function is directly inhibited by members of all three major classes of L-type Ca2+ channel antagonists.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Hargreaves AC,Gunthorpe MJ,Taylor CW,Lummis SCsubject
Has Abstractpub_date
1996-11-01 00:00:00pages
1284-94issue
5eissn
0026-895Xissn
1521-0111journal_volume
50pub_type
杂志文章abstract::The 5'-flanking region of the mouse mu opioid receptor (MOR) gene has two promoters, referred to as distal and proximal. MOR mRNA is predominantly initiated by the proximal promoter. Previously, several important cis-elements and trans-factors have been shown to play a functional role in the proximal promoter of the M...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008284
更新日期:2005-05-01 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::To determine the relationship between vascular alpha 1-adrenergic receptor occupancy and receptor-coupled calcium flux, we have studied [3H]prazosin binding and l-norepinephrine-induced 45Ca efflux in cultured vascular smooth muscle cells isolated from the rabbit aorta. In a crude cellular homogenate, [3H]prazosin bou...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-05-01 00:00:00
abstract::K-252b, a member of the staurosporine family of protein kinase inhibitors, selectively potentiates the activation of the nerve growth factor receptor, TrkA, by a nonpreferred ligand, neurotrophin-3 (NT-3), in a variety of cell types. At higher (micromolar) concentrations of K-252b, an inhibitory effect occurs because ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.56.1.185
更新日期:1999-07-01 00:00:00
abstract::Depending on their primary structure, the 28 mammalian transient receptor potential (TRP) cation channels identified so far can be sorted into 6 subfamilies: TRPC ("Canonical"), TRPV ("Vanilloid"), TRPM ("Melastatin"), TRPP ("Polycystin"), TRPML ("Mucolipin"), and TRPA ("Ankyrin"). The TRPV subfamily (vanilloid recept...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.109.055624
更新日期:2009-06-01 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::Liver homeostasis is achieved by the removal of diseased and damaged hepatocytes and their coordinated replacement to maintain a constant liver cell mass. Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means of removing the unwanted cells, and the Fas "death receptor" pa...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.005223
更新日期:2005-03-01 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 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
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::ATM and NBS1, mutation of which lead to the human autosomal recessive diseases ataxia telangiectasia and Nijmegen breakage syndrome (NBS), respectively, are essential elements in the cellular response to DNA damage induced by ionizing radiation (IR). ATM is a member of the phosphatidylinositol 3-kinase family and is a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.036681
更新日期:2007-08-01 00:00:00
abstract::The highly conserved Arg in the so-called DRY motif (Asp-Arg-Tyr) at the intracellular end of transmembrane helix 3 is in general considered as an essential residue for G protein coupling in rhodopsin-like seven transmembrane (7TM) receptors. In the open reading frame 74 (ORF74) receptor encoded by equine herpesvirus ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.011239
更新日期:2005-07-01 00:00:00
abstract::A series of isoflavone and tyrphostin compounds were found to inhibit the degradation of cAMP by several cyclic nucleotide phosphodiesterase (PDE) isozymes. Specific hydroxyl groups on the isoflavone structure were critical for PDE isozyme-selective inhibition. Replacement of the C-7 hydroxyl group of the isoflavone w...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.57.4.738
更新日期:2000-04-01 00:00:00
abstract::Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents. We have showed previously that recombinant (r) Hu BChE can be expressed at very high levels, 400 to 600 U/ml in mouse blood, by delivering the Hu BChE gene using adenovirus (Ad). Here, we repor...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.055665
更新日期:2009-09-01 00:00:00
abstract::Cardiac-directed expression of AC6 has pronounced favorable effects on cardiac function possibly not linked with cAMP production. To determine rigorously whether cAMP generation is required for the beneficial effects of increased AC6 expression, we generated a catalytically inactive AC6 mutant (AC6mut) that has marked...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.067298
更新日期:2011-03-01 00:00:00
abstract::The X-ray and NMR structural study of 3-carbomethoxy rifamycin S5 was undertaken in order to determine whether its low antimicrobial activity was related to a conformation of the molecule which was unfavorable for interaction with bacterial DNA-dependent RNA polymerase. However, the molecule assumes a conformation sim...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
abstract::The role of mitogen-activated protein kinase signaling and the transcription factor c-Jun in epidermal growth factor (EGF)-induced expression of 12-lipoxygenase in human epidermoid carcinoma A431 cells was studied. EGF increased the activation of extracellular signal-regulated kinase (ERK) and c-Jun amino terminal kin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2000-01-01 00:00:00
abstract::The binding kinetics of [3H]Ro 15-1788, a selective benzodiazepine receptor antagonist, to synaptosomal membranes of rat cerebral cortices was studied. [3H]Ro 15-1788 binds with high affinity (dissociation constant, 0.53 nM) to a single class of binding sites (maximal binding capacity, 1.97 pmoles/mg of protein). Equi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-03-01 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::Our previous studies suggested that the dNTP/dNDP transporter systems that exist in mitochondria for transporting dNTP/dNDP from the cytoplasm to the mitochondria for mitochondrial DNA (mtDNA) synthesis play a critical role in delayed cytotoxicity of anti-human immunodeficiency virus (HIV) dideoxynucleoside analogs in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.007120
更新日期:2005-02-01 00:00:00
abstract::Fusion proteins between the human 5-hydroxytryptamine (5-HT)(1A) receptor and either wild type or certain pertussis toxin-resistant forms of G(o1)alpha and G(i1)alpha display constitutive GTPase activity that can be inhibited by the inverse agonist spiperone. Addition of recombinant regulator of G protein signaling (R...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.5.1211
更新日期:2002-05-01 00:00:00
abstract::The rat mu-opioid receptor clone in which novel exon 5 was found in the place of exon 4 (MOR-1B) was one of the first MOR-1 variants described. We now have identified the mouse homolog of the rat MOR-1B as well as four additional variants derived from splicing from exon 3 into different sites within exon 5. The sequen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.011858
更新日期:2005-09-01 00:00:00
abstract::The new olivacine derivative S16020-2 (NSC-659687) is a DNA topoisomerase II inhibitor endowed with a remarkable antitumor activity against various experimental tumors. In vitro physicochemical properties of this compound, in particular its interaction with DNA and DNA topoisomerase II, were very similar to those of e...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.4.709
更新日期:2000-10-01 00:00:00
abstract::The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microM [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative Ca(2+)/calmodulin-dependent protein kinase I...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.2.328
更新日期:2000-08-01 00:00:00
abstract::The pharmacological preservation of bone in the ovariectomized rat by estrogen, selective estrogen receptor modulators (SERMs), and bisphosphonates has been well described. However, comprehensive molecular analysis of the effects of these pharmacologically diverse antiresorptive agents on gene expression in bone has n...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.011478
更新日期:2005-11-01 00:00:00
abstract::We have examined alpha1beta2gamma2L GABAA receptor modulation by the endogenous steroids allopregnanolone (3alpha5alphaP), pregnenolone sulfate, and beta-estradiol in the absence and presence of ethanol. Coapplication of 0.1 to 1% (17-170 mM) ethanol influenced receptor modulation by 3alpha5alphaP but not that by preg...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.029942
更新日期:2007-02-01 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::The membrane-permeable, noncompetitive inositol 1,4,5-trisphosphate (IP3)-receptor inhibitor 2-aminoethoxydiphenyl borane (2-APB) has been widely used to probe for IP3-receptor involvement in calcium signaling pathways. However, a number of recent studies in different cell types revealed other sites of action of 2-APB...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.6.1304
更新日期:2003-06-01 00:00:00
abstract::Iron is a biologically essential metal, but excess iron can cause damage to the cardiovascular and nervous systems. We examined the effects of extracellular Fe²⁺ on permeation and gating of Ca(V)3.1 channels stably transfected in HEK293 cells, by using whole-cell recording. Precautions were taken to maintain iron in t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080184
更新日期:2012-12-01 00:00:00
abstract::The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.065102
更新日期:2010-10-01 00:00:00