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At least 1,279 records · Page 71Linked to original sources
PubMed2003

Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves.

NIH3T3 cells stably expressing the rat 5-hydroxytryptamine 2A (5-HT 2A) receptor (5500 fmol/mg) were used to explore further the capacity of structurally distinct ligands to elicit differential signaling through the phospholipase C (PLC) or phospholipase A 2 (PLA 2) signal transduction pathways. Initial experiments were designed to verify that 5-HT 2A receptor-mediated PLA 2 activation in NIH3T3 cells is independent from, and not a subsequent result of, 5-HT 2A receptor-mediated PLC activation. In addition, we also explored the extent of receptor reserve for the endogenous ligand, 5-HT, for both PLC and PLA 2 activation. Finally, we employed structurally diverse ligands from the tryptamine, phenethylamine, and ergoline families of 5-HT 2A receptor agonists to test the hypothesis of agonist-directed trafficking of 5-HT 2A receptor-mediated PLC and PLA 2 activation. To measure agonist-induced pathway activation, we determined the potency and intrinsic activity of each compound to activate either the PLA 2 pathway or the PLC pathway. The results showed that a larger receptor reserve exists for 5-HT-induced PLA 2 activation than for 5-HT-induced PLC activation. Furthermore, the data support the hypothesis of agonist-directed trafficking in NIH3T3-5HT 2A cells because structurally distinct ligands were able to induce preferential activation of the PLC or PLA 2 signaling pathway. From these data we conclude that structurally distinct ligands can differentially regulate 5-HT 2A receptor signal transduction.

3T3 Cells↗
PubMed2000

Differential modes of agonist binding to 5-hydroxytryptamine(2A) serotonin receptors revealed by mutation and molecular modeling of conserved residues in transmembrane region 5.

Site-directed mutagenesis and molecular modeling were used to investigate the molecular interactions involved in ligand binding to, and activation of, the rat 5-hydroxytryptamine(2A) (5-HT(2A)) serotonin (5-HT) receptor. Based on previous modeling studies utilizing molecular mechanics energy calculations and molecular dynamics simulations, four sites (S239[5.43], F240[5.44], F243[5.47], and F244[5.48]) in transmembrane region V were selected, each predicted to contribute to agonist and/or antagonist binding. The F243A mutation increased the affinity of (+/-)4-iodo-2, 5-dimethoxyphenylisopropylamine, decreased the binding of alpha-methyl-5HT, N-omega-methyl-5HT, ketanserin, ritanserin, and spiperone and had no effect on the binding of 5-HT and 5-methyl-N, N-dimethyltryptamine. The F240A mutant had no effect on the binding of any of the ligands tested, whereas F244A caused an agonist-specific decrease in binding affinity (3- to 10-fold). S239A caused a 6- to 13-fold decrease in tryptamine-binding affinity and a 5-fold increase in affinity of 4-iodo-2, 5-dimethoxyphenylisopropylamine. A subset of the agonists used in binding studies were used to determine the efficacies and potencies of these mutants to activate phosphoinositide hydrolysis. The F243A and F244A mutations reduced agonist stimulated phosphoinositide hydrolysis, whereas the S239A and F240A mutations had no effect. There was little correlation between agonist binding and second messenger production. Furthermore, molecular dynamics simulations, considering these data, produced ligand-bound structures utilizing substantially different bonding interactions even among structurally similar ligands (differing by as little as one methyl group). Taken together, these results suggest that relatively minor changes in either receptor or ligand structure can produce drastic and unpredictable changes in both binding interactions and 5-HT(2A) receptor activation. Thus, our finding may have major implications for the future and feasibility of receptor structure-based drug design.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed2006

Atomic description of an enzyme reaction dominated by proton tunneling.

We present an atomic-level description of the reaction chemistry of an enzyme-catalyzed reaction dominated by proton tunneling. By solving structures of reaction intermediates at near-atomic resolution, we have identified the reaction pathway for tryptamine oxidation by aromatic amine dehydrogenase. Combining experiment and computer simulation, we show proton transfer occurs predominantly to oxygen O2 of Asp(128)beta in a reaction dominated by tunneling over approximately 0.6 angstroms. The role of long-range coupled motions in promoting tunneling is controversial. We show that, in this enzyme system, tunneling is promoted by a short-range motion modulating proton-acceptor distance and no long-range coupled motion is required.

Alcaligenes faecalis↗
PubMed1962

Urinary excretion of amines in phenylketonuria and mongolism.

Children with phenylketonuria excrete considerably less serotonin and tryptamine and somewhat less normetanephrine and p-tyramine than normal children. The excretion of these amines was not decreased in mongolism. Even during monoamine oxidase blockade, o-tyramine could not be detected in the urine of phenylketonurics. These findings are discussed in relation to the mental defect of phenylketonuria.

Amines↗
PubMed1973

Reduced monoamine oxidase activity in platelets: a possible genetic marker for vulnerability to schizophrenia.

Monoamine oxidase activity in blood platelets was measured, with [(14)C]tryptamine as substrate, in 13 monozygotic twin pairs discordant for schizophrenia and in 23 normal volunteers. The monoamine oxidase activity of both schizophrenic and nonschizophrenic co-twins was significantly lower than it was for the normals, and it was highly correlated between twins. In addition, there was a significant inverse correlation between a measure of the degree of the schizophrenic disorder and the monoamine oxidase activity. These data suggest, but do not prove, that reduced platelet monoamine oxidase activity may provide a genetic marker for vulnerability to schizophrenia.

Adult↗
PubMed2001

A role for flavin monooxygenase-like enzymes in auxin biosynthesis.

Although auxin is known to regulate many processes in plant development and has been studied for over a century, the mechanisms whereby plants produce it have remained elusive. Here we report the characterization of a dominant Arabidopsis mutant, yucca, which contains elevated levels of free auxin. YUCCA encodes a flavin monooxygenase-like enzyme and belongs to a family that includes at least nine other homologous Arabidopsis genes, a subset of which appears to have redundant functions. Results from tryptophan analog feeding experiments and biochemical assays indicate that YUCCA catalyzes hydroxylation of the amino group of tryptamine, a rate-limiting step in tryptophan-dependent auxin biosynthesis.

Alleles↗
PubMed1975

Formation of indoleacetic acid by intestinal anaerobes.

Indoleacetic acid was produced from tryptophan by only three of 23 intestinal anaerobes studied. Evidence is presented to show that the formation of indoleacetic acid proceeds through the intermediate, indolepyruvic acid, via transamination with alpha-ketoglutarate rather than by tryptamine pathway.

Anaerobiosis↗
PubMed1973

Involvement of a tryptophan residue in the assembly of bacteriophages 80 and lambda.

The assembly of infective particles of bacteriophages lambda and phi80 from heads and tails was found to be inhibited by l-tryptophan and some of its analogues, most notably tryptamine. Both the rate of assembly and the final yield of phage were inhibited. The amino acid l-phenylalanine had a slight inhibitory effect, whereas all other amino acids found in proteins were ineffective. Evidence was presented to show that the binding of heads to tails was the affected process in the assay for assembly of infective units. The plaque-forming ability of preassembled phage was not affected by these inhibitors. Results of three different types of experiments suggest that inhibition is due to interaction of inhibitors with the head substructure. The assembly reaction is highly dependent on pH, ionic strength, and the presence of detergents.

Binding Sites↗
PubMed1980

Tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human cerebrospinal fluid: interrelationships and the influence of age, sex, epilepsy and anticonvulsant drugs.

Tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid were measured in cerebrospinal fluid, taken during pneumoencephalography, from a large series of patients, the majority of whom were epileptics, most of them receiving anticonvulsants. CSF indoleacetic acid reflects CNS tyrptamine metabolism in the same way that CSF 5-hydroxyindoleacetic acid reflects CNS 5-hydroxytryptamine metabolism. Our data suggest that (i) the brain tryptophan content is an important factor in the control of both 5-hydroxytryptamine and tryptamine synthesis (ii) brain 5-hydroxytryptamine metabolism exhibits a U-shaped relationship with age (iii) the mean brain tryptophan content and rate of 5-hydroxytryptamine metabolism are greater for women than men (iv) indoleamine metabolism is unaffected in untreated epileptics compared with non-epileptics, but anticonvulsant drugs decrease the rate of 5-hydrosytryptamine metabolism.

Adult↗
PubMed1990

Forskolin-induced HCO3- current across apical membrane of the frog corneal epithelium.

Forskolin (and other Cl- secretagogues) does not affect the very small Na(+)-originated short-circuit current (Isc) across frog corneal epithelium bathed in Cl- free solutions. However, forskolin in combination with increased PCO2 bubbling of the solutions (5-20% CO2) stimulated Isc proportionally to PCO2 to a maximum of approximately 8 microA/cm2. This current could be eliminated and reinstated by sequentially changing the gas composition of the bubbling to 100% air and 20% CO2-80% air. The same effects were observed when PCO2 changes were limited to the apical-side solution. Stroma-to-tear HCO3- movement was deemed unlikely, since the increase in Isc was observed with a HCO3(-)-free solution on the stromal side and CO2 gassing limited to the tear side. From the effects of ouabain and tryptamine, at least 80% of the Isc across the basolateral membrane can be accounted for by the Na+ pump current plus K+ movement from cell to bath. Methazolamide also inhibited Isc. Current across the apical membrane cannot be attributed to an electronegative Na(+)-HCO3- symport given the insensitivity of Isc to a disulfonic stilbene and the fact that stroma-to-tear Na+ fluxes did not increase on stimulation of Isc. The tear-to-stroma Na+ flux also remained unaltered, negating an increased apical bath-to-cell Na+ flow. The forskolin-20% CO2 manipulation produced a depolarization of the intracellular potential, a reduction in the apical-to-basolateral resistance ratio, and a decrease in transepithelial resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1977

Neurophysiological measures and visual averaged evoked responses in psychiatric patients. Relationship to monoamine oxidase activity in platelets.

In 57 consecutive patients with psychiatric disorders correlations were sought between the neurophysiological variables - amplitudes and latencies of visual averaged evoked responses (VAER), the proneness to augment or to reduce the amplitude of VAER with increasing stimulus intensity, PAR and PRI, the mean integrated amplitude (MIA) and its within patient variance (WPV) and the monoamine oxidase activity (MAO) in platelets, both with beta-fenylethylamine (MAO1) and with tryptamine (MAO2) as substrate. When multiple correlations with age occurred, a multiple regression was calculated to evaluate the relative importance of each component. MAO1 was found to be significantly correlated to Ampl. N1 and Lat. 2, 3 and 4 of VAER while MAO2 only gave a significant correlation with LaT. 4. As in earlier studies Ampl. N1 was found to be significantly correlated to the content of 5-hydroxyindoleacetic acid in liquor, these measurements seem to be the most important in psychiatric disorders where the monoaminergic systems are supposed to be disturbed.

Adult↗
PubMed1977

MAO activity in rat brain stem and cerebral cortex following acute and chronic treatment with L-dopa and ethanol + L-dopa.

This work reports the effects of acute and chronic administration of L-dopa and ethanol + L-dopa on MAO activity in rat brain stem and cerebral cortex using noradrenaline (NA), dopamine (DA), serotonin (5-HT) and tryptamine (Try) as substrates. The results obtained clearly demonstrate that acute and chronic treatment affects MAO activities in the two brain areas examined in opposite ways. Moreover, the two treatments show different effects both according to the substrate used, and, especially in the case of NA and Try, according to the brain area examined.

Animals↗
PubMed1980

Twin studies and substrate differences in platelet monoamine oxidase activity.

Monoamine oxidase activity was measured in blood platelets of 7 pairs of identical (MZ) twins and a similar number of age- and sex-matched control pairs. Mean intrapair difference in platelet MAO activity was significantly smaller (0.01 less than p less than 0.025) in MZ compared to controls. Kinetic studies of the enzyme revealed mean Km value of 1.0 x 10(-5) mol/l for tryptamine. Platelet MAO activity is higher in women than in men.

Adolescent↗
PubMed1983

Patterns of monoamine oxidase maturation in mouse brain.

Monoamine oxidase (MAO) was assayed in mouse brain between the ages of 1 day postpartum and adulthood. Two substrates, 5-hydroxytryptamine (5-HT) and tryptamine, were used and assays were done with and without thermal inactivation at 50 degrees C for 10 min. Relative patterns of MAO maturation were found including one form that decreased with increasing age.

Age Factors↗
PubMed1981

Immunocytochemical detection of serotonin with monoclonal antibodies.

The development of the monoclonal antibody YC5/45 HLK (YC5/HLK) against a 5HT-bovine seroalbumin immunogen and its application for immunocytochemistry is described. The YC5/HLK antibody is the product of a rat x rat hybrid myeloma, producing a heavy chain and two light chains. In hemagglutination tests, the antibody cross-reacts to entirety with dopamine, serotonin, and tryptamine at high concentrations. The serotonin-albumin conjugate is 20,000 times more effective in displacing the binding antibody, while albumin itself goes unrecognized by the antibody. In fixed preparations of brain tissue, immunofluorescence is observed only in neurons known to contain serotonin, while no reaction is observed in dopamine-rich neurons. All immunofluorescence is extinguished by the use of agents that inhibit the biosynthesis of 5HT, but not of the catecholamines.

Animals↗
PubMed1976

Effect of carbidopa on prolactin, growth hormone and cortisol secretion in man.

Serum prolactin, growth hormone and cortisol levels were examined in normal volunteers following administration of carbidopa, a peripheral decarboxylase inhibitor. 24-hour urinary tryptamine levels dropped markedly indicating that inhibition of decarboxylase was effective. Prolactin levels rose while growth hormone and cortisol remained unchanged. Since the tuberoinfundibular dopamine nerve terminals lie outside the blood brain barrier, this study suggests that these neurons are involved in prolactin but not in growth hormone or cortisol regulation. Findings are compatible with two alternate hypotheses--either that dopamine is a physiologic prolactin inhibiting factor (PIF) or that tuberoinfundibular dopamine neurons regulate the release of PIF.

Adult↗