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At least 19 recordsLinked to original sources
PubMed1975

Thyrotropin receptors in thyroid plasma membranes. Characteristics of thyrotropin binding and solubilization of thyrotropin receptor activity by tryptic digestion.

Biologically active bovine 125I-thyrotropin preparations have been prepared, characterized, and used to evaluate the optimal conditions for thyrotropin binding to bovine thyroid plasma membranes in vitro. Binding of 125I-TSH has a pH optimum around 6.0 and is sensitive to the choice and concentration of buffer. Binding is inhibited by salts, especially those containing magnesium and calcium ions; magnesium concentrations optimal for adenylate cyclase assays (2 to 5 mM) result in 85 to 98% inhibition of binding. Binding is temperature sensitive. At 37 degrees binding has its highest initial level; however, instability of the membrane at this temperature causes a rapid loss of binding activity. Binding at 0 degrees is optimal in 30 min and at the same level as initial binding at 37 degrees; since there is no decrease in binding activity, it has been chosen as the optimal temperature. Thyrotropin, luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin have relative binding affinities for the thyrotropin receptors of 100, 10, 2, and less than 0.5, respectively. In all of these characteristics, 125I-thyrotropin at 1.5 x 10(-5) M concentrations has the same properties of binding to bovine plasma membranes as do [3H]thyrotropin preparations which have been previously characterized (Amir, S.M., Carraway, T.F., Jr., Kohn, L.D., and Winand, R.V. (1973) J. Biol. Chem. 248, 4092-4100) and used to study binding at 5 x 10(-6) M concentrations. 125I-TSH binding as a function of hormone concentration results in curved Scatchard plots; however, Hill plots of these same binding data are linear and have a slope of 0.65. Taken together, these data suggest that the heterogeneity in thyrotropin binding constants which is evident in the Scatchard plot reflects a negatively cooperative relationship among the thyrotropin receptor sites, i.e. decreased hormonal affinity as hormone concentrations increase. Adenylate cyclase studies yield kinetic plots which also exhibit negative cooperativity; corrections for thyrotropin bound under the adverse binding conditions of the adenylate cyclase assays suggest that Km values for thyrotropin in this enzymatic assay are compatible with binding constants measured by the 125I-thyrotropin preparations. Tryptic digestion destroys binding activity on the thyroid plasma membrane but releases specific thyrotropin receptor activity into the supernatant phase. Chromatography on Sephadex G-100 indicates that this solubilized receptor fragment has a molecular weight between 15,000 and 30,000.

Adenylyl Cyclases↗
PubMed1975

Thyrotropin effects on thyroid cells in culture. Effects of trypsin on the thyrotropin receptor and on thyrotropin-mediated cyclic 3':5'-AMP changes.

Dog, human, and bovine thyroid cells in culture have been shown to develop follicle-like structures when cells are cultured in conditions of confluency and when cells are incubated in the presence of bovine thyrotropin or N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate during the first 24 to 48 hours after trypsinization. If thyrotropin is added 48 hours after trypsinization, these cells do not form follicle-like structures but remain as a monolayer culture. Although thyroid cells which grow as a monolayer have a thyrotropin receptor on their plasma membranes with the same in vitro binding properties as the thyrotropin receptor on the plasma membranes of the follicle-forming thyroid cells, there is a 1- to 2-fold greater number of receptors per mg of membrane protein when follicle-forming and monolayer cultures are compared...

Animals↗
PubMed1979

Plasma thyrotropin-releasing hormone, prolactin, thyrotropin, and thyroxine concentrations following the intravenous or oral administration of thyrotropin-releasing hormone.

In a further evaluation of the use of oral thyrotropin-releasing hormone (TRH) in puerperally lactating women, a radioimmunoassay for its measurement has been developed. Its concentration in plasma as well as that of prolactin (PRL), thyrotropin (TSH) and thyroxine (T4) were measured following either intravenous or oral administration of TRH. Basal concentrations of TRH in 14 normally cycling women ranged from less than 5 to 17 pg/ml. Two luteal phase studies produced peaks in plasma TRH 5 to 10 minutes after 100 micrograms of TRH administered intravenously with a return to basal concentrations within 2 to 3 hours. In 10 normally menstruating women, ingestion of 10 mg of TRH orally resulted in plasma TRH which peaked at 423 +/- 123 pg/ml (standard error of the mean) at 30-minutes. Plasma PRL, TSH, and T4 also increased and remained slightly elevated at 4 hours. These 8-hour studies were performed in a puerperal lactating woman who had ingested 10 mg of TRH orally twice a day for 7 days prior to blood sampling. TRH concentrations declined throughout each day while TSH rose slightly in the first 1 to 2 hours but remained within normal limits. The prolonged administration of 10 mg of TRH orally twice daily to three puerperally lactating women resulted in elevations in plasma TRH 2 to 3 hours following hormone administration, yet no significant increases in plasma TSH were observed. Both endogenous TRH and TSH were measured before and after 22 nursing events in nine puerperally lactating women. There was no change in the concentration of either substance and all values were similar to those obtained in normally menstruating women.

Administration, Oral↗
PubMed1975

Experimental exophthalmos. Binding of thyrotropin and an exophthalmogenic factor derived from thyrotropin to retro-orbital tissue plasma membranes.

Biologically active preparations of 125I-thyrotropin, [3H]thyrotropin, and the [3H]exophthalmogenic factor derived from thyrotropin by partial pepsin digestion have been used to study the binding properties of the thyrotropin receptor on guinea pig retro-orbital tissue plasma membranes. In regard to the optimal conditions of binding, pH, buffer, salt concentrations, and temperature, these properties are the same as those described in any accompanying report concerning thyrotropin binding to bovine thyroid plasma membranes (Tate, R.L., Schwartz, H.I., Holmes, J.M., Kohn, L.D., and Winand, R.J. (1975) J. Biol. Chem. 250, 6509-6515). In addition, thyrotropin receptors on the retro-orbital tissue plasma membranes are similar to thyrotropin receptors on bovine thyroid plasma membranes in their apparent negative cooperativity and in their relative affinities for luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin. In contrast, gamma-globulin from patients with malignant exophthalmos enhances binding when added to incubation mixtures containing the retro-orbital tissue plasma membranes but not when added to those containing thyroid plasma membranes. Normal gamma-globulin and gamma-globulin from Graves' disease patients without exophthalmos do not have this property. The gamma-globulin itself does not bind to the membrane except in the presence of thyrotropin or its exophthalmogenic factor derivative. Tryptic digestion of the retro-orbital tissue membranes releases specific thyrotropin and exophthalmogenic factor binding activity into the supernatant phase. Chromatography on Sephadex G-100 indicates that this trypsin-released receptor activity has a molecular weight of 75,000 or greater, rather than 15,000 to 30,000 for the trypsin-released receptor activity from bovine thyroid membranes (Tate, R.L., Schwartz, H.I., Holmes, J.M., Kohn, L.D., and Winand, R.J. (1975) J. Biol. Chem. 250, 6509-6515).

Animals↗
PubMed1976

Relationship of gangliosides to the structure and function of thyrotropin receptors: their absence on plasma membranes of a thyroid tumor defective in thyrotropin receptor activity.

Plasma membranes derived from rat thyroid tumor (1-8R) which is unresponsive to thyrotropin but is responsive to dibutyryl adenosine 3':5'-cyclic monophosphate bind less than 20% of the [125I] thyrotropin which can be bound to plasma membranes from normal rat thyroids under conditions which optimize tumor membrane binding relative to normal thyroid membranes. In addition, the binding is different from thyrotropin binding to normal thyroid membranes both in its altered sensitivity to changes in hydrogen ion concentration and in a decreased sensitivity to competition by unlabeled thyrotropin. This reduced capacity to bind [125I] thyrotropin cannot be attributed to degradation of the hormone by membrane-associated proteases. Although the supernatant phase of the thyroid tumor homogenates contains a soluble component which inhibits [125I] thyrotropin binding to thyrotropin receptors on plasma membranes, its level is the same as in homogenates of normal thyroid tissue. Trypsin digestion does not expose thyrotropin receptors in a manner analogous to that seen in normal thyroid tissue. The major ganglioside in the tumor membranes is N-acetylneuraminylgalactosylglucosylceramide and the membranes lack the N-acetylgalactosaminyltransferase required for the synthesis of more complex gangliosides. In contrast, the normal rat thyroid membranes contain more complex gangliosides such as galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide and N-acetylneuraminylgalactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosyl ceramide as well as the glycosyltransferase activities required for their syntheses. Galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide can also be detected in normal membranes, but not in tumor membranes, by selective labeling with galactose oxidase (D-galactose: oxygen 6-oxidoreductase, EC 1.1.3.9) and [3H] sodium borohydride. These results support the hypothesis that gangliosides are important structural or functional components of thyrotropin receptors on thyroid plasma membranes.

Animals↗
PubMed1976

Thyrotropin-ganglioside interactions and their relationship to the structure and function of thyrotropin receptors.

Gangliosides inhibit 125I-labeled thyrotropin binding to the thyrotropin receptors on bovine thyroid plasma membranes, on guinea pig retro-orbital tissue plasma membranes, and on human adipocyte membranes. This inhibition by gangliosides is critically altered by the number and location of the sialic acid residues within the ganglioside structure, the efficacy of inhibition having the following order: GD1b greater than GT1 greater than GM1 greater than GM2 = GM3 greater than GD1a. The inhibition results from the interaction of thyrotropin and gangliosides, rather than the interaction of membrane and gangliosides. Fluorescence studies show that the inhibition is associated with a distinct conformational change of the thyrotropin molecule and that the progression from a "noninhibitory conformation" to an "inhibitory conformation" parallels exactly the order of effectiveness in inhibiting 125I-labeled thyrotropin binding. The ganglioside inhibition of 125I-labeled thyrotropin binding appears to be hormonally specific in that it is not affected by albumin, glucagon, insulin, prolactin, follicle-stimulating hormone, growth hormone, or corticotropin. The possibility that a ganglioside or ganglioside-like structure is a component of the thyrotropin receptor is suggested by the finding that gangliosides more complex than N-acetylneuraminylgalactosylglucosylceramide are present in bovine thyroid membranes in much higher quantities than have been previously found in extraneural tissue. The finding that the B component of cholera toxin, which also interacts with gangliosides, has a peptide sequence in common with the beta subunit of thyrotropin, suggests that thyrotropin and cholera toxin may be analogous in their mode of action on the membrane.

Adipose Tissue↗
PubMed1979

The interaction of radioiodinated thyrotropin with human plasma membranes from normal and diseased thyroid glands. Relation of thyrotropin binding to adenylate cyclase activity.

Plasma membranes have been purified from homogenates of normal human thyroid glands and multinodular euthyroid and Graves' goitres by discontinuous sucrose gradient centrifugation. Preparations of reasonable purity were obtained containing specific binding sites for thyrotropin and thyrotropin-sensitive adenylate cyclase. Optimum conditions for 125I-labeled thyrotropin binding were pH 7.8 and 37 degrees C. Sodium ions and concentration of Tris above 20 mM reduced thyrotropin binding. Human plasma membranes showed no species specificity toward thyrotropins from 3 different species (ox, hog and man). Displacement curves of I125-labeled bovine thyrotropin by unlabeled hormones was in the order of increasing concentrations of bovine, porcine and human highly purified thyrotropins and was inversely related to the specific biological activity of these preparations as determined by the bioassay in the mouse. Analysis of the interaction between membranes and 125I-labeled thyrotropin resulted in curvilinear Scatchard plots which can indicate the presence of two types of sites with high affinity -- low capacity (KD = 5 nM) and low affinity -- high capacity (KD = 500 nM) or site -- site interaction of the negative cooperativity type. No significant difference in binding site characteristics was found in normal and diseased glands (multinodular and Graves' goitres). A good correlation was found at equilibrium and in the conditions of adenylate cyclase assay between receptor occupancy and cyclase activation by b-thyrotropin.

Adenylyl Cyclases↗
PubMed1975

Stimulation of adenylate cyclase activity in retro-orbital tissue membranes by thyrotropin and an exophthalmogenic factor derived from thyrotropin.

Retro-orbital tissue membranes have been shown to have adenylate cyclase activity which can be stimulated by thyrotropin and by an exophthalmogenic factor derived from the thyrotropin molecule by partial pepsin digestion. This stimulable activity is maximal after 15 min and is optimal in the presence of 3 mM magnesium and 1.5 mM ATP. Calcium salts are exquisitely inhibitory to the hormonal stimulation; sodium, lithium, and ammonium salts are significantly less inhibitory. Thyrotropin and the exophthalmogenic factor induce similar maximal levels of stimulation but a 4- to 5-fold higher concentration of exophthalmogenic factor is required to achieve this level. Fluoride stimulates adenylate cyclase activity 2- to 3-fold higher than either thyrotropin or the exophthalmogenic factor; thyrotropin, luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin have relative activities for stimulation of cyclase activity of 100:2:2 less than 0.5. Several other polypeptide and glycoprotein hormones have no effect. The gamma-globulin from patients with malignant exophthalmos has no significant effect on cyclase activity either alone or in the presence of maximal levels of thyrotropin or the exophthalmogenic factor; this gamma-globulin does, however, stimulate cyclase activity at submaximal hormone levels. Trypsin not only destroys the hormone-stimulable adenylate cyclase activity on retro-orbital tissue plasma membranes, but also destroys it on the 15,000 to 30,000 molecular weight receptor fragment released from the membranes by the tryptic action.

Adenylyl Cyclases↗
PubMed1977

Effects of thyrotropin and thyroid hormones in vivo on thyroid responsiveness to thyrotropin in vitro.

The thyroid gland of rats fed propylthiouracil is known to be unresponsive in vitro to thyrotropin; to investigate further the underlying mechanism groups of rats were variously treated with propylthiouracil and thyroid hormone or subjected to hypophysectomy. In vitro responsiveness of the thyroids was tested by measuring an increase in the concentration of c AMP when thyrotropin or prostaglandin E1 was added to the medium. Results showed that responsiveness to thyrotropin partially returned with rats fed prophylthiouracil and hypophysectomized 5, but not 2, days before death; hypophysectomy of normal rats led to increased in vitro responsiveness to thyrotropin and this was partially reversed by injections of thyrotropin for a week before death. Administration of thyroid hormone had little effect in these investigations and in vitro responsiveness to prostaglanding E1 was not consistently influenced by any of the in vivo regimens. From this experience we conclude that, at least as studied in vitro, circulating thyrotropin has a significant role in modulating responsiveness of the thyroid to thyrotropin.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Unchanged thyrotropin and prolactin responses to thyrotropin releasing hormone after indomethacin treatment.

Experimental effects of prostaglandin synthetase inhibitors have been considered in the literature as a clue to the possible interactions of prostaglandins with the hypothalamic releasing hormones at the pituitary level. Some results of the administration to man of these drugs are apparently in contrast with the in vivo and in vitro animal data. The present investigation deals with the comparison between the thyrotropin releasing hormone (TRH) effect on prolactin and thyrotropin when the hormone was administered intravenously at doses of 50, 100 and 200 microgram respectively to three groups of six men (aged 22 to 30 years), before and on the sixth day of indomethacin administration (50 mg orally at 6-hour intervals). No significant change in the releasing hormone effect was observed either in the case of prolactin, where TRH caused a consistently similar release of the hormone at every dose employed, or in the case of thyrotropin, where a dose-dependent releasing effect was obtained before and after indomethacin treatment.

Adult↗
PubMed1978

Suppression of serum thyrotropin (TSH) concentrations following thyroidectomy and cold exposure by passive immunization with antiserum to thyrotropin-releasing hormone (TRH) in rats.

Administration of antiserum to synthetic thyrotropin-releasing hormone (TRH) to thyroidectomized rats caused a significant depression of serum thyrotropin (TSH). Serum TSH and triiodothyronine (T3) responses to cold exposure (4 +/- 1 C) were abolished by administration of anti-TRH serum. In addition, synthetic TRH lost its biological activity when bound to the gamma globulin fraction from the anti-TRH serum. These observations provide evidence that TRH is involved in the mechanism of enhanced TSH secretion from the pituitary following thyroidectomy and cold exposure.

Animals↗
PubMed1978

Thyrotropin and prolactin secretory patterns during 24-hours infusion of thyrotropin-releasing hormone in calves.

Plasma levels of thyrotropin (TSH), prolactin (Prl), growth hormone (GH), thyroxine (T4), and triiodothyronine (T3) were measured in response to continuous 24-h infusion of synthetic thyrotropin-releasing hormone (TRH) in normal and surgically thyroidectomized (THYX) calves in a series of 2 experiments. In the 1st experiment, the low dose of TRH (0.077 microgram/min) had no effect on any hormone levels measured. Plasma TSH concentration increased significantly (p less than 0.05) in response to TRH infusion (0.77 microgram/min) in both experiments, but plasma TSH levels plateaued and then declined in both cases despite continued TRH infusion and irrespective of the presence or absence of a thyroid gland. A similar pattern of secretion, though less markedly decreased over time, was observed for plasma Prl in both experiments. The higher dose (0.77 microgram/min) of TRH had no effect on plasma GH concentration in the 1st infusion, but did result in a significant (p less than 0.05) increase in overall mean concentration of GH in both normal and THYX calves in the 2nd experiment. Removal of the thyroid gland, thus removing the source of increasing T4 and T3 levels seen in normal calves infused with TRH, failed to alter the secretory patterns of TSH and Prl. These data suggest that feedback inhibition by increasing plasma thyroid hormone concentrations was not responsible for the failure of TSH and, to a lesser extent, Prl to maintain chronically elevated plasma levels in response to continuous 24-h TRH infusion. It is suggested that a depletion of pituitary TSH and Prl stores readily secretable in response to a constant dosage level of TRH may be responsible for the secretory patterns observed.

Animals↗
PubMed1978

Thyrotropin, prolactin and growth hormone response to synthetic thyrotropin-releasing hormone in newborn infants.

The effects of 50 microgram synthetic thyrotropin-releasing hormone (TRH) intravenously on thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) levels were studied in 8 normal male newborns during the first hours of life. Mean plasma GH concentrations were similar to baseline values during the period of study; on the contrary, plasma PRL and TSH values increased in all infants after TRH administration. These data demonstrate a normal pituitary reserve of PRL and TSH in the early period of human life.

Growth Hormone↗
PubMed1977

Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: relationship to spinal fluid amine metabolites.

The authors studied pituitary thyrotropin, i.e., thyroid-stimulating hormone (TSH), response to thyrotropin-releasing hormone (TRH) in patients with primary affective disorder. There were no overall differences between either depressed or manic patients and normal controls; however, the TSH response was significantly lower in the unipolar depressed patients than in either bipolar depressed patients or normal subjects. Bipolar patients in the manic phase tended to have a lower response than bipolar depressed patients. In the unipolar group, the TSH response showed a significant negative correlation with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. These neuroendocrine responses may constitute markers of specific monoamine dysfunction in subgroups of patients with affective illness.

Age Factors↗
PubMed1977

Suppression of prolactin and thyrotropin secretion in the rat by antiserum to thyrotropin-releasing hormone.

Administration of antiserum to synthetic thyrotropin-releasing hormone (TRH) to male and female rats cause a 50% and a 70% suppression in serum levels of prolactin and thyrotropin, respectively, as compared with controls injected with normal rabbit serum. The degree of suppression was similar in diestrous and proestrous female rats and in male rats. These findings support the view that, in addition to its original designation, TRH also has a physiological role in regulating release of pituitary prolactin.

Animals↗