Abstract:
:Amphetamine congeners [e.g., 3,4-methylenedioxymetamphetamine (MDMA), or "ecstasy"] are substrates for monoamine transporters (i.e., the transporters for serotonin, norepinephrine, and dopamine); however, their in vivo-action relies on their ability to promote monoamine efflux. The mechanistic basis for this counter transport remains enigmatic. We tested the hypothesis that outward transport is contingent on the oligomeric nature of neurotransmitter transporters by creating a concatemer of the serotonin transporter and the amphetamine-resistant GABA transporter. In cells expressing the concatemer, amphetamine analogs promoted GABA efflux and blunted GABA influx. In contrast, the natural substrates serotonin and GABA only cause mutual inhibition of influx via the other transporter moiety in the concatemer. GABA efflux through the concatemer that was promoted by amphetamine analogs was blocked by the protein kinase C inhibitors GF109203X (bisindoylmaleimide I) and Go6983 (2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide). Thus, based on our observations, we propose that, in the presence of amphetamine analogs, monoamine transporters operate as counter-transporters; influx and efflux occur through separate but coupled moieties. Influx and efflux are coupled via changes in the ionic gradients, but these do not suffice to account for the action of amphetamines; the activity of a protein kinase C isoform provides a second stimulus that primes the inward facing conformation for outward transport.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Seidel S,Singer EA,Just H,Farhan H,Scholze P,Kudlacek O,Holy M,Koppatz K,Krivanek P,Freissmuth M,Sitte HHdoi
10.1124/mol.67.1.keywords:
subject
Has Abstractpub_date
2005-01-01 00:00:00pages
140-51issue
1eissn
0026-895Xissn
1521-0111pii
67/1/140journal_volume
67pub_type
杂志文章abstract::To study the molecular pharmacology of low-voltage-activated calcium channels in biophysical detail, human medullary thyroid carcinoma (hMTC) cells were investigated using the single-channel technique. These cells had been reported to express T-type whole-cell currents and a Ca(v)3.2 (or alpha 1H) channel subunit. We ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.3.682
更新日期:2002-03-01 00:00:00
abstract::The gonadotropin-releasing hormone receptor (GnRH-R) of the African catfish couples to phospholipase C and belongs to the large family of G protein-coupled receptors. We recently demonstrated that removal of the carboxyl-terminal tail (S331-Q379) from the catfish GnRH-R results in a loss of agonist binding; the curren...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.56.6.1229
更新日期:1999-12-01 00:00:00
abstract::Ca-dependent, K-stimulated 86Rb efflux, a measure of Ca-activated K conductance in rat brain synaptosomes, was blocked by phenothiazines and haloperidol. Micromolar concentrations of the phenothiazines, fluphenazine and trifluoperazine, and haloperidol, a non-phenothiazine antipsychotic and calmodulin antagonist, sele...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-02-01 00:00:00
abstract::Cross-talk between G protein-coupled receptors and protein tyrosine kinases is well established, but the phenotypic consequences of these signaling interactions are not completely understood. To investigate the role of Src family kinases in mitogenic signaling by G protein-coupled receptors, we used genetic and pharma...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.010546
更新日期:2005-06-01 00:00:00
abstract::Rat and human lung microsomal cytochrome P-450 (P-450) enzymes have been characterized with regard to their catalytic activities towards several xenobiotic chemicals, including procarcinogens, in different microsomal preparations. Rat lung microsomal P-450s were more active than the human P-450s in catalyzing most of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract::In standard 3H-opioid binding assays, the benzoylhydrazone derivative of naloxone (6-desoxy-6-benzoylhydrazido-N-allyl-14-hydroxydihydronormorphi none; NalBzoH) inhibited mu, kappa, and delta binding at nanomolar concentrations. At concentrations as low as 1 nM, it also produced a wash-resistant inhibition of opioid b...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-01-01 00:00:00
abstract::Secreted R-spondin proteins (RSPOs1-4) function as adult stem cell growth factors by potentiating Wnt signaling. Simultaneous binding of distinct regions of the RSPO Fu1-Fu2 domain module to the extracellular domains (ECDs) of the LGR4 G protein-coupled receptor and the ZNRF3 transmembrane E3 ubiquitin ligase regulate...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.114.095133
更新日期:2015-01-01 00:00:00
abstract::A site-directed alkylating agent was used to inactivate one or more types of opioid receptor in two bioassay preparations in the presence of type-selective ligands as protectors of other opioid receptor types. Since the pharmacological potency of an agonist is decreased when the receptor type through which it acts has...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-05-01 00:00:00
abstract::Vinflunine, the newest fluorinated Vinca alkaloid, currently in phase III clinical trials, targets the microtubule network to induce mitotic block and apoptosis by mechanisms that remain unclear. In the current study, we investigated the apoptotic pathways induced by a wide range of vinflunine concentrations in SK-N-S...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.66.3.
更新日期:2004-09-01 00:00:00
abstract::We have, in the accompanying work, demonstrated the coexistence of M2 and M3 muscarinic receptors in the circular smooth muscle of canine colon. In the present study, the effects of muscarinic receptor stimulation on phosphoinositide turnover and adenylate cyclase activity were examined. In myo-[3H]inositol-labeled ci...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-12-01 00:00:00
abstract::Accumulated evidence suggests that dopamine and dopamine D1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought to be linked to adenylyl cyclase, has...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.1.6
更新日期:1997-01-01 00:00:00
abstract::The relations between the single high affinity binding sites for azapropazone, phenylbutazone, chlorpropamide, sulfathiazole, and iophenoxate and the binding regions of human serum albumin represented by the marker ligands diazepam, phenol red, salicylate, and warfarin were examined by a series of competition experime...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-08-01 00:00:00
abstract::Amitriptyline is a classic tricyclic antidepressant (TCA) and has been used to treat the depression and anxiety of patients with cancer, but its relevance to cancer cell apoptosis is not known. In the present study, we demonstrated that amitriptyline inhibited cyclin D2 transactivation and displayed potential antimyel...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.068122
更新日期:2011-04-01 00:00:00
abstract::Inflammation contributes to pain hypersensitivity through multiple mechanisms. Among the most well characterized of these is the sensitization of primary nociceptive neurons by arachidonic acid metabolites such as prostaglandins through G protein-coupled receptors. However, in light of the recent discovery that the no...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.040832
更新日期:2008-02-01 00:00:00
abstract::Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.033928
更新日期:2007-06-01 00:00:00
abstract::Recombinant interferon-alpha (IFN) enhances the cytotoxic effects of the fluorinated pyrimidine, 5-fluorouracil (5FU), against two human colon cancer cell lines. The aspartate transcarbamylase (ATCase) inhibitor, N-(phosphonacetyl)-L-aspartate (PALA), was studied in combination with 5FU/IFN to determine whether furthe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-11-01 00:00:00
abstract::Binding by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor leads to transcriptional activation of several genes and a toxicity syndrome that includes tumor promotion, wasting, hormonal and immune system dysfunction, and death. Recent findings indicate that TCDD may also affect cardiac function. Here, we ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-12-01 00:00:00
abstract::The mouse 5-hydroxytryptamine4a (5-HT4a) receptor is an unusual member of the G protein-coupled receptor superfamily because it possesses two separate carboxyl-terminal palmitoylation sites, which may allow the receptor to adopt different conformations in an agonist-dependent manner (J Biol Chem 277:2534-2546, 2002). ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008748
更新日期:2005-05-01 00:00:00
abstract::Many progestins have been developed for use in contraception, menopausal hormone therapy, and treatment of gynecological diseases. They are derived from either progesterone or testosterone, and they act by binding to the progesterone receptor (PR), a hormone-inducible transcription factor belonging to the nuclear rece...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.054312
更新日期:2009-06-01 00:00:00
abstract::Stimulatory effects of spermine at heteromeric N-methyl-D-aspartate (NMDA) receptors expressed from cloned subunits were studied by voltage-clamp recording in Xenopus oocytes. At NR1A/NR2B receptors, in the presence of a saturating concentration of glycine, the magnitude of spermine stimulation was dependent on the co...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-07-01 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 GABA type A receptor (GABA(A)R) is the major inhibitory receptor in the mammalian central nervous system and the target of numerous pharmaceuticals. The alpha-subunit of these pentameric Cys-loop neurotransmitter-gated ion channels contributes to the binding of both GABA and allosteric modulators such as the benzo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.059832
更新日期:2010-07-01 00:00:00
abstract::The interaction between two nonhomologous K+ channel toxins, Tityus serrulatus (scorpion) toxin tityustoxin-K alpha (TsTX-K alpha) and Dendroaspis angusticeps (snake) toxin dendrotoxin (alpha-DTX), was investigated on K+ currents in B82 fibroblast cells transformed to express the Kv1.2 K+ channel. As demonstrated prev...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-08-01 00:00:00
abstract::The immunosuppressive agent cyclosporine A has been shown to reverse multidrug resistance (MDR) in malignant cells. In the present study, a 3H-cyclosporine diazirine analogue was used to photolabel viable MDR Chinese hamster ovary cells. The 170-kDa membrane P-glycoprotein, which functions as a drug efflux pump, was s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-10-01 00:00:00
abstract::We have synthesized and characterized a high-affinity alpha 1-adrenergic receptor probe, 4-amino-6,7-dimethoxy-2[4'- [5"(3"'-125I-iodo-4"'-aminophenyl)pentanoyl]-1'-piperazinyl] quinazoline (125I-A55453). This ligand binds reversibly to rat hepatic plasma membranes with high affinity (KD = 77 +/- 6 pM), and it labels ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-09-01 00:00:00
abstract::Multidrug resistance-associated protein 2 (MRP2) transports glutathione conjugates, glucuronide conjugates, and sulfated conjugates of bile acids. In the present study, we examined the role of charged amino acids in the transmembrane domains of rat Mrp2, conserved among MRP families, using the isolated membrane vesicl...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.5.1077
更新日期:2001-05-01 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 ADP-sensitive and K+ -sensitive phosphorylated forms of Na,K-ATPase (E1P and E2P, respectively) are believed to be the main phosphorylated intermediates of Na,K-ATPase. In the presence of 100 mM Na+, E2P is the major component of the phosphorylated form in all native Na,K-ATPase preparations known, including the m...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-11-01 00:00:00
abstract::Trypanosoma brucei encodes a relatively high number of genes of the equilibrative nucleoside transporter (ENT) family. We report here the cloning and in-depth characterization of one T. brucei brucei ENT member, TbNT9/AT-D. This transporter was expressed in Saccharomyces cerevisiae and displayed a uniquely high affini...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.031559
更新日期:2007-03-01 00:00:00
abstract::Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma ce...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-04-01 00:00:00