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  • 1
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; human ; SYSTEM ; SITE ; GENE ; GENES ; HYBRIDIZATION ; SAMPLE ; PATIENT ; COMPLEX ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; DISORDER ; polymorphism ; VARIANTS ; TARGET ; IN-SITU ; ASSAY ; MUTATION ; genetics ; etiology ; REGION ; REGIONS ; REPLICATION ; HEALTHY ; LUCIFERASE ; heredity ; ANTAGONIST ; MANAGEMENT ; molecular biology ; molecular ; DISORDERS ; VARIANT ; NEURONS ; analysis ; EPITHELIUM ; pooled analysis ; HTR3A ; ENGLAND ; MUTATION ANALYSIS ; DYSFUNCTION ; UNTRANSLATED REGION ; POOLED-ANALYSIS ; UK ; 5-HT3 ; ABDOMINAL-PAIN ; ALOSETRON
    Abstract: Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G 〉 A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G 〉 A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G 〉 A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D
    Type of Publication: Journal article published
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  • 2
    ISSN: 1433-0474
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The dependence on Na+, K+, and C1− of uptake and accumulation of [3H]noradrenaline was studied in plasma membrane vesicles isolated from PC-12 pheochromocytoma cells. Plasma membrane vesicles accumulated [3H]noradrenaline when an inward-directed gradient for Na+ and an outward-directed gradient for K+ were imposed across the vesicle membrane. Under these conditions, initial rates of uptake of [3H]noradrenaline were saturable (Km= 0.14 μM) and inhibited by a series of substrates and inhibitors of “uptake1.’ The IC50 values were positively correlated with those for inhibition of uptake into intact PC-12 cells. Uptake and accumulation [3H]noradrenaline in plasma membrane vesicles were absolutely dependent on external Na+ and C1−; they were dependent on an inwardly directed gradient for Na+ but less dependent on an inwardly directed gradient for C1−. Internal K+ strongly enhanced uptake and accumulation of [3H]noradrenaline. Rb+, but not Li+, had the capacity to replace internal K+. Two explanations are proposed for this effect of internal K+: (a) creation of a K+ diffusion potential (inside negative) provides a driving force for inward transport, and/or (b) K+ increases the turnover rate by formation of a highly mobile potassium–carrier complex. A hypothetical scheme for the transport of noradrenaline is presented.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1474-8673
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1912
    Keywords: Isoprenaline ; Extraneuronal uptake ; Corticosterone ; Inhibition of extraneuronal uptake ; Extraneuronal efflux ; Steady-state kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To simultaneously determine the kinetics of removal, O-methylation and accumulation of 3H-isoprenaline, isolated rat hearts were perfused for 4 min with various concentrations of 3H-isoprenaline. The apparent K m for the O-methylation of 3H-isoprenaline (3.3±0.5 μM) was more than one order of magnitude lower than the corresponding value for the accumulation of unchanged amine (71.3±7.1 μM). The apparent K m for removal was very similar to that for accumulation (63.2±5.9 μM). At perfusion concentrations higher than 25 μM, i.e. when O-methylation was saturated, removal virtually equalled accumulation. However, at low substrate concentrations removal of 3H-isoprenaline was overwhelmingly followed by O-methylation; this led to a marked difference between rates of removal and those of accumulation. When initial rates of uptake of 3H-isoprenaline were determined after 1.5 min of perfusion of the hearts by the method of Graefe et al. (1978), the uptake of 3H-isoprenaline consisted of two components: a nonsaturable and a saturable (after subtraction of the nonsaturable component from the total uptake). The kinetic constants of the saturable component of uptake were higher than those obtained after 4 min perfusion (see above) (K m : 110±19 μM; V max: 80±4 nmoles·g−1·min−1). Corticosterone competitively inhibited the saturable component of uptake of 3H-isoprenaline (K m : 1.2 μM). During wash out of accumulated 3H-isoprenaline, O-methylation took place predominantly in one of the two extraneuronal compartments. The efflux of 3-O-methyl-3H-isoprenaline (3H-OMI), the O-methylated metabolite of 3H-isoprenaline, was characterized by a half time of about 1.2 min. O-methylation accelerated the loss of radioactivity from the tissue during wash out. The extraneuronal uptake of 3H-isoprenaline was characterized as a “pump and leak” system by means of steady-state kinetics of accumulation of 3H-isoprenaline. Half saturation of the steady-state accumulation was observed at a concentration of 104.5 ±18.5 μM 3H-isoprenaline; the leak component was characterized by a rate constant of 0.0359 min−1.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1912
    Keywords: Rate constant for efflux of amine ; Isoprenaline ; Simulated efflux curves ; Extraneuronal mechanism ; Mathematical model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Rat hearts were perfused with 0.1 μM 3H-isoprenaline for 10 min in the presence of 10 μM U-0521 to inhibit catechol-O-methyl transferase (COMT) and then washed out with amine-free solution. Analysis of efflux curves revealed a preferential filling of one (compartment III) of the two extraneuronal compartments described by Bönisch et al. (1974). U-0521 inhibited the efflux of isoprenaline from compartment III. Omission of U-0521 from the wash out solution quickly restored COMT activity. It was then possible to determine the rate constant for the efflux (k s) of isoprenaline from rate of efflux and amine content of tissue. 2. A procedure is developed which permits the calculation of k s from efflux curves for amine and metabolite without any need for determining the amine content of the tissue. With this procedure, k s can be determined even when there is a “bound fraction” (i.e., a second compartment, the amine content of which does not contribute to the experimentally determined efflux). The procedure is based on the fact that, for a single compartment in which the amine is metabolized and from which there is efflux of amine and metabolite, parallel efflux curves (i.e., plots of log rate of efflux against time) are obtained, if the rate constant for the efflux of the metabolite (k p) is higher than the rate constant for the loss of amine from the compartment (k system). The activity of the metabolizing enzyme determines k system and the ratio “initial rate of efflux of metabolite/initial rate of efflux of amine” (F 0). 3. A mathematical model (simulating metabolism in, and efflux of amine and metabolite from a single compartment) was used to determine the distortion of F 0 by “k system/k P” (when k P limits the efflux of the metabolite). An estimate of k s obtained from F 0 and from k system agrees well with the estimate of k s obtained directly (see 1, above).
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1912
    Keywords: 22Na influx ; Superior cervical ganglion ; Cholinomimetics ; Tyrosine hydroxylase induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Isolated superior cervical ganglia of the rat were incubated for 2–30 min (37°C) in Krebs' solution or tissue culture medium (BGJb) containing 22Na and then washed for 30 min in ice-cold 22Na-free Krebs' solution (to clear the extracellular space). The radioactivity remaining in the ganglia was taken as a measure of 22Na influx into the intracellular compartment of the ganglion. 2. Addition of cholinomimetics (100 μM nicotine or 100 μM carbachol) to the incubation medium led to an increase in 22Na influx. This increase reached maximal values after 10 min of incubation; it was more pronounced after incubation in Krebs' solution than in BGJb medium. 3. While chlorisondamine (3 μM) or dopamine (100 μM) greatly reduced the carbachol-induced 22Na influx, tetrodotoxin (2 μM) did not have any effect. 4. In ganglia obtained from animals treated with 6-hydroxydopamine in the early postnatal phase (resulting in an extensive destruction of peripheral sympathetic neurons) neither carbachol (100 μM) nor nicotine (100 μM) produced an increase in 22Na influx demonstrating that the intraneuronal compartment is responsible for this enhanced influx. 5. The effects of dopamine, chlorisondamine and tetrodotoxin on the carbachol-induced 22Na uptake into superior cervical ganglia are similar to their effects on carbachol-mediated induction of tyrosine hydroxylase in superior cervical ganglia kept in tissue culture (Thoenen and Otten 1977b). It is concluded that the induction of tyrosine hydroxylase via nicotinic receptors is closely linked to the enhanced sodium influx into the adrenergic neurons mediated by the same receptors.
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  • 9
    ISSN: 1432-1912
    Keywords: (+)-amphetamine ; Neuronal uptake ; Sympathomimetic amines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary PC-12 cells (a clonal line of rat phaeochromocytoma cells) take up noradrenaline by a transport system which is identical with the neuronal amine transport system (“uptake1”). The uptake of 3H-noradrenaline into reserpine-pretreated PC-12 cells (monoamine oxidase inhibited) was saturable (Km=0.6±0.1 μmol/l), dependent on sodium and chloride, and competitively inhibited by (+)-amphetamine (Ki=0.18±0.04 μmol/l), cocaine (Ki=0.55±0.15 μmol/l) and desipramine (Ki=4.3±0.6 nmol/l). The uptake and accumulation of 3H (+)-amphetamine showed characteristics comparable to those of 3H-noradrenaline, since the uptake of 3H (+)-amphetamine (0.1 μmol/l) was reduced by omission of sodium or chloride from the incubation medium. The sodium-sensitive component of uptake and accumulation of 3H (+)-amphetamine was fully inhibited by cocaine and desipramine. The IC50 of desipramine for inhibition of the sodium-sensitive component of the 1-min uptake of 3H (+)-amphetamine (20 nmol/l) was about 2 nmol/l, i.e., identical with the Ki for inhibition of uptake of 3H-noradrenaline. At concentrations above 1 μmol/l, desipramine additionally caused an inhibition of the sodium-independent permeation of 3H (+)-amphetamine into PC-12 cells. Hence, by using a homogeneous population of cells endowed with “uptake1”, it is possible to demonstrate — besides a pronounced lipophilic entry — a carrier-mediated uptake of 3H (+)-amphetamine.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1912
    Keywords: Uptake1 ; Desipramine binding ; PC12 Cells ; N-Ethylmaleimide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The inhibition by N-ethylmaleimide (NEM) of uptake1 and desipramine binding was studied on clonal rat phaeochromocytoma cells (PC12 cells) in different experimental settings: (1) 3H-noradrenaline uptake into intact PC12 cells; (2) 3H-noradrenaline uptake into isolated PC12 plasma membrane vesicles; (3) 3H-desipramine binding to isolated PC12 plasma membrane vesicles. In plasma membrane vesicles, NEM inhibited 3H-desipramine binding and 3H-noradrenaline uptake with similar potency (the IC50's were 1.36 mmol/l and 1.04 mmol/l, respectively). However, in intact cells, NEM was about 75 times more potent in inhibiting 3H-noradrenaline uptake (IC50 = 0.014 mmol/l). The increased potency of NEM in intact cells is probably due to an inhibition of the Na+/K +-ATPase and not to a direct interaction with the noradrenaline carrier. The inactivation by NEM of 3H-desipramine binding to PC12 plasma membrane vesicles was irreversible. Both an inhibitor (cocaine, 1 mmol/l) and a substrate of uptake1 (amezinium, 1 mmol/l) protected desipramine binding from inactivation. These results are compatible with the hypothesis of a common binding site for substrates and inhibitors of the neuronal noradrenaline carrier.
    Type of Medium: Electronic Resource
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