Abstract:
:The heart is richly endowed with K(ATP) channels, which function as biological sensors, regulating membrane potentials and electrical excitability in response to metabolic alterations. We recently reported that the cytochrome P450 metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), potently activate cardiac K(ATP) channels by reducing channel sensitivity to ATP. In the present study, we further demonstrate that 11(S),12(R)-EET activated the cardiac K(ATP) channels with an EC(50) of 39.5 nM, whereas 11(R),12(S)-EET was totally inactive. In addition, 11(S),12(R)-EET but not 11(R),12(S)-EET hyperpolarized the resting membrane potentials and shortened the duration of cardiomyocyte action potentials. By studying homologs and analogs of 11,12-EET, we also found that all four EET regioisomers are equipotent activators of the K(ATP) channels, reducing the ATP sensitivity by more than 10-fold; however, neither altered chain length, double bond number, epoxide position, nor methylation of the carboxyl group affected channel inhibitions by ATP. All the fatty epoxides studied are potent K(ATP) channel activators, but the omega-3 homolog was particularly potent, reducing ATP sensitivity 27-fold. Together, the results indicate that the presence of an epoxide group in a particular three-dimensional configuration is a critical determinant for K(ATP) channel activation, and its effect is augmented by a double bond at omega-3 position. The results also suggest that fatty epoxides are important modulators of cardiac electrical excitability.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Lu T,VanRollins M,Lee HCdoi
10.1124/mol.62.5.1076keywords:
subject
Has Abstractpub_date
2002-11-01 00:00:00pages
1076-83issue
5eissn
0026-895Xissn
1521-0111journal_volume
62pub_type
杂志文章abstract::The effects of single and repeated electroconvulsive shock (ECS) on the binding of [3H]diprenorphine to rat brain membranes was studied. Repeated but not single ECS significantly increased the Bmax of [3H]diprenorphine binding when measured in the absence but not in the presence of NaCl. On a regional basis the effect...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-05-01 00:00:00
abstract::Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed usi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.009373
更新日期:2005-07-01 00:00:00
abstract::Prior studies indicate that adenosine and the adenosine A2A receptor play a role in hepatic fibrosis by a mechanism that has been proposed to involve direct stimulation of hepatic stellate cells (HSCs). The objective of this study was to determine whether primary hepatic stellate cells produce collagen in response to ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.038760
更新日期:2007-12-01 00:00:00
abstract::We have investigated the effect of chronic flurazepam HCl treatment on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic flurazepam (1-5 microM, for 1-10 days) treatment did not produce any changes in the morphological appearance or the cell protein content of cortica...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-04-01 00:00:00
abstract::Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the ...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.109.063172
更新日期:2010-06-01 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::Recently, inositol hexakisphosphate (phytic acid) was shown to bind to photoreceptor arrestin and block its interaction with rhodopsin. Such an interaction might predict that inositol polyphosphates could alter G protein-coupled receptor desensitization. To investigate the possible roles of higher inositol polyphospha...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-08-01 00:00:00
abstract::Two structural models have been developed to explain how agonist binding leads to ionotropic glutamate receptor (iGluR) activation. At alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) iGluRs, full and partial agonists close the agonist-binding domain (ABD) to different degrees whereas agonist-induced do...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.054254
更新日期:2009-05-01 00:00:00
abstract::Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K+ channels. Here, we homology-modeled voltage- and Ca2+-gated K+ channel BK and voltage-gated Kv1.3 using the X-ray structures of MthK and Kv1.2, respectively, and simulated the binding of d-tubocurarine in th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.017970
更新日期:2006-04-01 00:00:00
abstract::Maurotoxin (MTX) is a potent blocker of human voltage-activated Kv1.2 and intermediate-conductance calcium-activated potassium channels, hIKCa1. Because its blocking affinity on both channels is similar, although the pore region of these channels show only few conserved amino acids, we aimed to characterize the bindin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.002774
更新日期:2004-11-01 00:00:00
abstract::The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and different...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/molpharm.120.000006
更新日期:2020-11-01 00:00:00
abstract::The N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors are known to be inhibited by 3-amino-1-hydroxy-2-pyrrolidone (HA-966) and 7-chlorokynurenic acid (Cl-KYN), which act at the glycine-regulated allosteric modulatory center. In this work we show that, in synaptic membranes prepared from rat brain, Cl-KYN and ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-12-01 00:00:00
abstract::When exposed to the beta-agonist (-)-isoproterenol, rat glioma C6 cells exhibited a time-and concentration-dependent reduction in isoproterenol responsiveness (desensitization) and a loss of beta-adrenergic receptors (down-regulation). Other agents, such as dibutyryl cyclic AMP, isobutylmethylxanthine, and cholera tox...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-09-01 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::Using [3H]leukotriene C4 (LTC4) and radioligand-binding techniques, specific leukotriene C4 binding sites have been identified in membranes derived from guinea pig ventricular myocardium. High performance liquid chromatography analyses indicated that, in the presence of the gamma-glutamyl transpeptidase inhibitor L-se...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-02-01 00:00:00
abstract::Cells of the murine neuroblastoma clone N1E-115 possess muscarinic receptors that influence the intracellular level of cyclic nucleotides. The stimulation of [3H]cyclic GMP levels occurs only with intact cells and has an EC50 near the "low-affinity" agonist equilibrium dissociation constant (KL) determined by radiolig...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-09-01 00:00:00
abstract::Cannabinoids have been implicated in the reduction of glioma growth. The present study investigated a possible relationship between the recently shown induction of cyclooxygenase (COX)-2 expression by the endocannabinoid analog R(+)methanandamide [R(+)-MA] and its effect on the viability of H4 human neuroglioma cells....
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.002618
更新日期:2004-12-01 00:00:00
abstract::In the present study we have investigated the capacity of various compounds sterically related to indolo[3,2-b]carbazole to inhibit specific 2,3,7,8-tetrachloro[1,6-3H]dibenzo-p-dioxin binding in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gels. When the two nitrogen atoms of indolo[3,2-b]carba...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-08-01 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::Cocaine use poses a major health problem not only because of the dependence it causes but also because of the generation of life-threatening cardiac arrhythmias following overdose. Elucidating the molecular mechanisms of action of cocaine, therefore, remains a critical step in developing treatment for cocaine addictio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.56.6.1138
更新日期:1999-12-01 00:00:00
abstract::Mitsuya and Broder [Proc. Natl. Acad. Sci. USA 83:1911-1915 (1986)] demonstrated that every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside containing the 2',3'-dideoxyribose configuration, when evaluated against human immunodeficiency virus (HIV) in vitro, significantly s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-10-01 00:00:00
abstract::A family of five cholinergic muscarinic receptor genes (m1, m2, m3, m4, and m5) has recently been identified and cloned. In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00
abstract::Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]ph...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.104679
更新日期:2016-11-01 00:00:00
abstract::Smad4, a key transcription factor in the transforming growth factor-β signaling pathway, is involved in a variety of cell physiologic and pathologic processes. Here, we characterized megakaryocyte/platelet-specific Smad4 deficiency in mice to elucidate its effect on platelet function. We found that megakaryocyte/plate...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107417
更新日期:2017-09-01 00:00:00
abstract::Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-09-01 00:00:00
abstract::Studies in vertebrate neuromuscular synapses have revealed previously that ATP, via P2Y receptors, plays a critical role in regulating postsynaptic gene expressions. An equivalent regulatory role of ATP and its P2Y receptors would not necessarily be expected for the very different situation of the brain synapses, but ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.066506
更新日期:2010-12-01 00:00:00
abstract::Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. H...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/molpharm.120.000079
更新日期:2021-01-01 00:00:00
abstract::The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming growth factor (TGF)-beta 1 on cytochrome P-450 (CYP) 1A expression and polycyclic aromatic hydrocarbon (PAH)-mediated induction in primary human hepatocyte cultures were determined...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-12-01 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::Both in vivo and in vitro treatments with the irreversible protein-modifying reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), were used to investigate rat striatal D1 dopamine receptor/effector interactions. Peripherally administered EEDQ markedly reduced D1 dopamine receptor binding and D1 dopamine rec...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-01-01 00:00:00