Abstract:
:The ability of four antidepressant drugs, imipramine, alaproclate, norzimelidine, and fluvoxamine, to inhibit serotonin transport into platelet plasma membrane vesicles was tested over a range of external Na+ concentrations. Imipramine affinity, as we previously reported [J. Biol. Chem. 258:6115-6119 (1983)] increases sigmoidally with Na+. When measured by inhibition of serotonin transport, the affinity for alaproclate and norzimelidine is much less sensitive to Na+ and fluvoxamine actually inhibits more avidly at lower Na+. All of the drugs competitively inhibit serotonin transport. Moreover, alaproclate, norzimelidine, and fluvoxamine all competitively displace [3H]imipramine from platelet plasma membranes. The Ki for fluvoxamine inhibition of transport is 16-fold higher than its Ki for inhibition of imipramine binding. In contrast, alaproclate inhibits transport at concentrations lower than those required to block imipramine binding. In the case of fluvoxamine, and possibly also alaproclate, these differences are not due to separate sites mediating substrate and imipramine binding but rather to differences in the nature of binding and transport measurements. The results suggest that these antidepressant drugs and serotonin all bind to the same site, or to overlapping sites on the serotonin transporter, or to sites on the transporter whose occupation is mutually exclusive with substrate site occupation. The observation that binding of each ligand reacts differently to changes in Na+ suggests that distinct subsites are involved in each case. As reported previously by Wennogle and Myerson [Eur. J. Pharmacol. 86:303-307 (1983)] serotonin decreases the rate of imipramine dissociation from human platelet membranes. This effect is not observed in porcine platelets, is not Na+ dependent, and requires serotonin concentrations over 100 times the Km for transport. It is likely, therefore, to result from serotonin binding to a site distinct from the transport active site.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Humphreys CJ,Levin J,Rudnick Gsubject
Has Abstractpub_date
1988-06-01 00:00:00pages
657-63issue
6eissn
0026-895Xissn
1521-0111journal_volume
33pub_type
杂志文章abstract::Cholinesterase inhibitors are commonly used to improve cognition and treat psychosis and other behavioral symptoms in Alzheimer's disease, Parkinson's disease, and other neuropsychiatric conditions. However, mechanisms may exist that down-regulate the synaptic response to altered cholinergic transmission, thus limitin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.6.1309
更新日期:2003-12-01 00:00:00
abstract::Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M(1) muscarinic receptor agonist from a novel st...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.6.1297
更新日期:2002-06-01 00:00:00
abstract::We present a mechanism for agonist-promoted alpha(2A)-adrenergic receptor (alpha(2A)-AR) activation based on structural, pharmacological, and theoretical evidence of the interactions between phenethylamine ligands and alpha(2A)-AR. In this study, we have: 1) isolated enantiomerically pure phenethylamines that differ b...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.5.1343
更新日期:2001-05-01 00:00:00
abstract::The cannabinoid analog abnormal cannabidiol [abn-cbd; (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB(1) or CB(2) receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive, and is i...
journal_title:Molecular pharmacology
pub_type: 评论,杂志文章
doi:10.1124/mol.63.3.699
更新日期:2003-03-01 00:00:00
abstract::N-formyl peptide receptor (FPR1) and N-formyl peptide receptor-like 1 (FPRL1, now known as FPR2) are G protein-coupled receptors involved in host defense and sensing cellular dysfunction. Because of the potential for FPR1/FPR2 as a therapeutic target, our recent high-throughput screening efforts have focused on the id...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.060673
更新日期:2010-02-01 00:00:00
abstract::Ryanodine receptors (RyRs) are intracellular membrane channels playing key roles in many Ca(2+) signaling pathways and, as such, are emerging novel therapeutic and insecticidal targets. RyRs are so named because they bind the plant alkaloid ryanodine with high affinity and although it is established that ryanodine pro...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.114.093757
更新日期:2014-09-01 00:00:00
abstract::The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the developme...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.089532
更新日期:2014-02-01 00:00:00
abstract::Catecholamine transporters constitute the biological targets for several important drugs, including antidepressants, cocaine, and related compounds. Some information exists about discrete domains of these transporters that are involved in substrate translocation and uptake blockade, but delineation of domains mediatin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.6.1404
更新日期:2000-12-01 00:00:00
abstract::The hexapeptide [pGlu6,Pro9]substance P (SP)6-11, septide, has been shown to be an agonist as potent as SP in eliciting smooth muscle contraction in several in vitro preparations, while being a poor competitor of labeled SP binding. These results, as well as other pharmacological data, have suggested the existence of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-02-01 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::The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The most potent compound of this series, 5-(4-phenylbutoxy)psoralen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.6.1364
更新日期:2004-06-01 00:00:00
abstract::MicroRNAs (miRNAs) have emerged as a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. Over 700 miRNAs have been identified and sequenced in humans, and the number of miRNA genes is estimated at more than 1000. I...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.111.073528
更新日期:2011-10-01 00:00:00
abstract::The aim of this study was to use pharmacological inhibition of protein kinase A and mutation of potential protein kinase A phosphorylation sites to determine the role of protein kinase A-catalyzed phosphorylation of the dopamine D(1) receptor in agonist-stimulated desensitization and internalization of the receptor. T...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.4.806
更新日期:2002-04-01 00:00:00
abstract::Resistance to cisplatin, one of the most widely used anticancer chemotherapeutic agents, is a major clinical problem. There is no effective way to predict development of cisplatin resistance in cancers. As determined by reverse transcription-polymerase chain reaction and Western blotting, the expression of gamma-caten...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.5.1217
更新日期:2004-05-01 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::The dopamine D3 receptor, although structurally similar to the dopamine D2 receptor, has 100-fold higher affinity for agonists such as dopamine and quinpirole, when these receptors are expressed in 293 cells. Additionally, the D3 receptor has generally lower affinity for several antagonists than does the D2 receptor. ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-08-01 00:00:00
abstract::Acetylsalicylic acid (aspirin) is a cyclooxygenase (COX) inhibitor, yet some of its therapeutic effects are thought to derive from mechanisms unrelated to prostaglandin synthesis inhibition. In human intestinal myofibroblasts, aspirin, at therapeutic doses, had the unexpected effect of inducing prolonged COX-2 express...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.2.470
更新日期:2004-02-01 00:00:00
abstract::The mechanisms underlying mastoparan-induced elevation of the intracellular free calcium concentration ([Ca2+]i) were investigated in the insulin-secreting cell lines RINm5F and HIT. In both cell types, micromolar concentrations of mastoparan induced a prompt increase of [Ca2+]i, measured as an increase in fura-2 fluo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract::The small GTPase Rac1 has been widely implicated in mammary tumorigenesis and metastasis. Previous studies established that stimulation of ErbB receptors in breast cancer cells activates Rac1 and enhances motility via the Rac-guanine nucleotide exchange factor P-Rex1. As the Janus tyrosine kinase 2 (Jak2)/signal trans...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.084293
更新日期:2013-05-01 00:00:00
abstract::Formyl peptide receptor (FPR) and formyl peptide receptor like 1 (FPRL1) play important roles in inflammation and immunity. Stimulation of FPR and FPRL1 initiates a cascade of signaling events, leading to activation of various phagocyte responses, including chemotaxis, superoxide generation, and exocytosis. Trp-Lys-Ty...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.4.841
更新日期:2003-10-01 00:00:00
abstract::It has been demonstrated previously that cannabinol (CBN) differentially modulates interleukin-2 (IL-2) protein secretion by T cells with a corresponding change in extracellular signal-regulated kinase activity. The objective of the present studies was to further investigate the molecular mechanism by which CBN enhanc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.2.446
更新日期:2002-02-01 00:00:00
abstract::The biliary excretion of several organic anions is mediated by the canalicular multispecific organic anion transporter (cMOAT), which is hereditarily defective in mutant rats such as Eisai hyperbilirubinemic rats (EHBR). In addition, using a kinetic study with isolated canalicular membrane vesicles, we recently sugges...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-06-01 00:00:00
abstract::Functional coupling between muscarinic (m3) receptors and two voltage-gated K+ (Kv) channels (Kv1.2 and Kv1.5) cloned originally from canine colonic smooth muscle was studied using the Xenopus oocytes expression system and a mammalian cell line (COS cells). Oocytes were coinjected with cRNAs encoding the human m3 rece...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-12-01 00:00:00
abstract::Ubiquitination plays a crucial role in regulating protein turnover. Here we show that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance. We found that P-glycoprotein was constitutively ubiquit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.001966
更新日期:2004-09-01 00:00:00
abstract::Retina from 1-day-old chicks is a valuable tissue model for studying neuronal nicotinic receptors because it expresses a large number of the developmentally regulated high affinity [(3)H]epibatidine labeled nicotinic receptors. Most of these receptors contain the beta4 subunit associated with different alpha subunits....
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.6.1410
更新日期:2001-06-01 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::Regulator of G protein signaling (RGS) proteins are a family of approximately 20 proteins that negatively regulate signaling through heterotrimeric G protein-coupled receptors. The RGS proteins act as GTPase-activating proteins (GAPs) for certain Galpha subunits and as effector antagonists for Gqalpha. Mouse RGS14 enc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.3.569
更新日期:2000-09-01 00:00:00
abstract::Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentra...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-04-01 00:00:00
abstract::Previous biochemical studies have demonstrated that synergy between non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI) and nucleoside RT inhibitors (NRTIs) is due to inhibition by the NNRTI of the rate at which HIV-1 RT facilitates ATP-mediated excision of NRTIs from chain-terminated template/primers (T/P). ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.038596
更新日期:2008-02-01 00:00:00
abstract::The therapeutic potential of antitumor drugs is seriously limited by the manifestation of cellular drug resistance. We used the budding yeast Saccharomyces cerevisiae as a model system to identify novel mechanisms of resistance to one of the most active anticancer agents, cisplatin. We pinpointed NPR2 (nitrogen permea...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.2.259
更新日期:2003-08-01 00:00:00