Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cultured human umbilical vein endothelial cells, 5-HT and alpha-methyl 5-HT stimulated [45Ca2+] uptake in concentration-dependent manner, whereas the 5-HT1 agonists, m-CPP (1-(3-chlorophenyl)piperazine and 2-MPP (1-(2-methoxyphenyl)piperazine), were without effect. In turn, 5-HT-stimulated [45Ca2+] uptake was inhibited in concentration-dependent manners by the 5-HT receptor antagonists ketanserin (5-HT2), LY 53,857 (5-HT2) and methiothepine (5-HT1/2) and to a lesser degeree by MDL 72222 (5-HT3) and BRL 43694 (5-HT3) whereas (+/-)-propranolol (5-HT1) was without effect. These data indicate that 5-HT stimulates Ca2+ uptake by endothelial cells via activation of a 5-HT2 receptor subtype. 5-HT was without effect on de novo prostacyclin (PGI2) synthesis over the concentration of 5-HT that elicited [45Ca2+] uptake. Since 5-HT did not stimulate PGI2, an event associated with an increase in levels of intracellular Ca2+, it is postulated that the uptake of 45Ca2+ reflects changes of Ca2+ at the level of the plasma membrane rather than on intracellular changes. 5-HT-stimulated Ca2+ uptake may be of relevance to endothelium-dependent relaxation, vascular permeability and endothelial repair and proliferation.
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PMID:5-Hydroxytryptamine stimulates 45Ca2+ uptake by human umbilical vein endothelial cells in culture: mediation by 5-HT2 receptor subtypes. 151 43

The binding of a series of phenylpiperazines (3) and benzoylpiperazines (4) to central serotonin (5-HT) sites was investigated. Several derivatives of 3 displayed nanomolar affinities for 5-HT1 sites, whereas derivatives of 4 were essentially inactive both at 5-HT1 and 5-HT2 sites. 1-(2-Methoxyphenyl)piperazine (2-MPP, 3a) was found to possess an affinity (Ki = 35 nM) for 5-HT1 sites comparable to that of the recognized 5-HT agonist 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (Ki = 20 nM); 3a also displayed a 100-fold selectivity for 5-HT1 sites (as compared to 8-fold for TFMPP). In tests of stimulus generalization using rats trained to discriminate TFMPP (ED50 = 0.17 mg/kg) from saline, 3a was found to be nearly equipotent (ED50 = 0.22 mg/kg) with the training drug. These results suggest that 3a may be a novel and more selective 5-HT1 agonist than TFMPP.
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PMID:Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents. 370 81

Serotonin antibodies (SAb) were found in the blood sera of middle-aged and elderly parkinsonian patients. The incidence of Sab in young and middle-aged healthy subjects was less, but increasing with age. Injected into the rabbit caudate nuclei, Sab suppressed the main pathogenetic mechanism of parkinsonian syndrome, the generator of pathologically enhanced excitation (GPEE) and parkinsonian symptoms induced by the MPP injection into substantia nigra. The intracaudate injection of serotonin enhanced GPEE activity and parkinsonian syndrome. The role of serotoninergic system and Sab in parkinsonism is discussed.
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PMID:[Serotonin antibodies and their possible role in parkinsonism]. 790 Apr 44

Degeneration of serotonergic fibers in the rat striatum was produced by local administration of the serotonergic neurotoxin 5, 7-dihydroxytryptamine (5,7-DHT) or the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which is also toxic to serotonergic neurons. One week before neurotoxin administration, fibroblasts engineered to express the human BDNF gene were grafted into the mesencephalon, dorsal to the substantia nigra. Rats implanted with fibroblasts expressing the LacZ gene were used as controls, as well as sham-operated animals (not injected with any neurotoxin). After a survival period of 1 week, the serotonergic innervation of the striatum was assessed by measuring serotonin (5-HT) content and by immunohistochemical detection of 5-HT positive fibers. BDNF-producing cells prevented the striatal 5-HT loss induced by local administration of either 5,7-DHT or MPP(+), as well as the striatal dopamine (DA) loss induced by the latter neurotoxin. Grafting of fibroblasts carrying the BDNF or the Lac-Z gene did not modify striatal 5-HT or DA content in sham-operated animals. In 5, 7-DHT-lesioned rats, implanted or not with control Lac-Z fibroblasts, a striking reduction in the density of 5-HT immunoreactive fibers was observed. By contrast, the density of 5-HT fibers was similar in rats implanted with BDNF-producing fibroblasts as compared to sham-operated controls. The protective effect of BDNF on the damage to serotonergic terminals induced by the two neurotoxins suggests the interest of this neurotrophin in the treatment of behavioral disorders associated to neurodegenerative diseases.
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PMID:Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum. 1076 6

Quantitative aspects of inward and outward transport of substrates by the human plasmalemmal serotonin transporter (hSERT) were investigated. Uptake and superfusion experiments were performed on human embryonic kidney 293 cells permanently expressing the hSERT using [(3)H]serotonin (5-HT) and [(3)H]1-methyl-4-phenylpyridinium (MPP(+)) as substrates. Saturation analyses rendered K(m) values of 0.60 and 17.0 microM for the uptake of [(3)H]5-HT and [(3)H]MPP(+), respectively. Kinetic analysis of outward transport was performed by prelabeling the cells with increasing concentrations of the two substrates and exposing them to a saturating concentration of p-chloroamphetamine (PCA; 10 microM). Apparent K(m) values for PCA induced transport were 564 microM and about 7 mM intracellular [(3)H]5-HT and [(3)H]MPP(+), respectively. Lowering the extracellular Na(+) concentrations in uptake and superfusion experiments revealed differential effects on substrate transport: at 10 mM Na(+) the K(m) value for [(3)H]5-HT uptake increased approximately 5-fold and the V(max) value remained unchanged. The K(m) value for [(3)H]MPP(+) uptake also increased, but the V(max) value was reduced by 50%. When efflux was studied at saturating prelabeling conditions of both substrates, PCA as well as unlabeled 5-HT and MPP(+) (all substances at saturating concentrations) induced the same efflux at 10 mM and 120 mM Na(+). Thus, notwithstanding a 50% reduction in the V(max) value of transport into the cell, MPP(+) was still able to induce maximal outward transport of either substrate. Thus, hSERT-mediated inward and outward transport seems to be independently modulated and may indicate inconsistencies with the classical model of facilitated exchange diffusion.
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PMID:Quantitative analysis of inward and outward transport rates in cells stably expressing the cloned human serotonin transporter: inconsistencies with the hypothesis of facilitated exchange diffusion. 1130 96

Human embryonic kidney 293 (HEK-293) cells stably transfected with the human serotonin (5-HT) or dopamine transporter (hSERT, hDAT), or the rat GABA transporter GAT-1 were incubated with saturating concentrations of transporter substrates (hSERT: [(3)H]5-HT, [(3)H]N-methyl-phenyl-pyridinium (MPP+); hDAT: [(3)H]dopamine, [(3)H]MPP(+); rGAT: [(3)H]GABA). Uptake velocities decreased significantly over time for [(3)H]5-HT and [(3)H]dopamine (already visible at 1 min), but not for [(3)H]MPP(+) or [(3)H]GABA. In efflux experiments cells were preloaded and substrate diffusion into the medium was studied following the addition of appropriate uptake inhibitors. Fractional effluxes were (% min(-1)) 1.27, 0.72, 0.27 and 0.08 for [(3)H]5-HT, [(3)H]dopamine, [(3)H]MPP(+) and [(3)H]GABA, respectively. The results suggest that in uptake experiments the more lipophilic substrates [(3)H]5-HT and [(3)H]dopamine leave the cells by diffusion already after a short time (1 min) of accumulation.
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PMID:Substantial loss of substrate by diffusion during uptake in HEK-293 cells expressing neurotransmitter transporters. 1151 69

The 5-hydroxytryptamine type 2A (5-HT(2A)) receptor and the 5-HT(2C) receptor are closely related members of the G-protein-coupled receptors activated by serotonin that share very similar pharmacological profiles and cellular signaling pathways. These receptors express a canonical class I PDZ ligand (SXV) at their C-terminal extremity. Here, we have identified proteins that interact with the PDZ ligand of the 5-HT(2A) and 5-HT(2C) receptors by a proteomic approach associating affinity chromatography using immobilized synthetic peptides encompassing the PDZ ligand and mass spectrometry. We report that both receptor C termini interact with specific sets of PDZ proteins in vitro. The 5-HT(2C) receptor but not the 5-HT(2A) receptor binds to the Veli-3.CASK.Mint1 ternary complex and to SAP102. In addition, the 5-HT(2C) receptor binds more strongly to PSD-95 and MPP-3 than the 5-HT(2A) receptor. In contrast, a robust interaction between the 5-HT(2A) receptor and the channel-interacting PDZ protein CIPP was found, whereas CIPP did not significantly associate with the 5-HT(2C) receptor. We also show that residues located at the -1 position and upstream the PDZ ligand in the C terminus of the 5-HT(2A) and 5-HT(2C) receptors are major determinants in their interaction with specific PDZ proteins. Immunofluorescence and electron microscopy studies strongly suggested that these specific interactions also take place in living cells and that the 5-HT(2) receptor-PDZ protein complexes occur in intracellular compartments. The interaction of the 5-HT(2A) and the 5-HT(2C) receptor with specific sets of PDZ proteins may contribute to their different signal transduction properties.
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PMID:The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. 1498 5

The physiological function of neurotransmitter transporter proteins like the serotonin transporter (SERT) is reuptake of neurotransmitter that terminates synaptic serotoninergic transmission. SERT can operate in reverse direction and be induced by SERT substrates including 5-HT, tyramine and the positively charged methyl-phenylpyridinium (MPP(+)), as well as the amphetamine derivatives para-chloroamphetamine (pCA) and methylene-dioxy-methamphetamine (MDMA). These substrates also induce inwardly directed sodium currents that are predominantly carried by sodium ions. Efflux via SERT depends on this sodium flux that is believed to be a prerequisite for outward transport. However, in recent studies, it has been suggested that substrates may be distinct in their properties to induce efflux. Therefore, the aim of the present study was a pharmacological characterization of different SERT substrates in uptake experiments, their abilities to induce transporter-mediated efflux and currents. In conclusion, the rank order of affinities in uptake and electrophysiological experiments correlate well, while the potencies of the amphetamine derivatives for the induction of efflux are clearly higher than those of the other substrates. These discrepancies can be only explained by mechanisms that can be induced by amphetamines. Therefore, based on our pharmacological observations, we conclude that amphetamines distinctly differ from non-amphetamine SERT substrates.
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PMID:Serotonin-transporter mediated efflux: a pharmacological analysis of amphetamines and non-amphetamines. 1618 23

Two sets of new o-methoxyphenylpiperazine (MPP; series a) and 1,2,3,4-tetrahydroisoquinoline (THIQ; series b) derivatives, containing various imide moieties derived from NAN190, were synthesized and evaluated in vitro for their ability to bind to the serotonin 5-HT(1A) and 5-HT(2A) receptors. All new derivatives from series a demonstrated high 5-HT(1A) affinities, whereas THIQ analogues were much less active. With respect to 5-HT(2A) receptors, three MPP derivatives presented moderate activity but the rest of the investigated compounds were practically inactive. The influence of changes in terminus geometry on 5-HT(1A) receptor affinity was analyzed in regard to model compounds NAN190and MM199.
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PMID:New imide 5-HT1A receptor ligands - modification of terminal fragment geometry. 1800 21

The sodium-dependent transporters for dopamine, norepinephrine, and serotonin that regulate neurotransmission, also translocate the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)). Previous studies implicated residues in transmembrane helix (TMH) XI of DAT as important sites for MPP(+) transport. We examined the importance of TMH XI residues F551 and F556 for MPP(+) translocation by human SERT. Mutations at hSERT F556, but not F551, reduced both 5-HT and MPP(+) transport compared to wild type. However, F556S/hSERT showed a reduction in surface expression explaining the decrease of transport activity for 5-HT, but did not account for the decrease in MPP(+) transport observed. Cysteine mutants at those positions confirmed the accessibility of hSERT/F556 to different methanethiosulfonate (MTS) reagents, suggesting its presence in a hydrophilic environment of the protein. In the presence of MTSET, current induced by 5-HT and MPP(+) was inhibited at the F556C mutant. In agreement with our homology model of SERT, based on the leucine transporter (LeuT(Aa)) from Aquifex aeolicus structure, these results are consistent with the hypothesis that a portion of TMH XI lines the entrance into the substrate permeation pathway.
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PMID:Helix XI contributes to the entrance of the serotonin transporter permeation pathway. 1862 41


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