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PubMed1987

Electroconvulsive shock stimulates polyphosphoinositide degradation and inositol trisphosphate accumulation in rat cerebrum: lithium pretreatment does not potentiate these changes.

Using an in vivo model, we explored the acute effects of electroconvulsive shock (ECS) and lithium on rat cerebral polyphosphoinositides and inositol phosphates. ECS was shown to increase the [3H]inositol trisphosphate ([3H]IP3) by 75%, decrease the endogenous mass of phosphatidylinositol 4,5-bisphosphate (PIP2) by 23%, and enhance [3H]myo-inositol labeling into the polyphosphoinositides. In contrast, lithium pretreatment 20-24 h prior to ECS appeared to attenuate the ECS-induced [3H]IP3 increase and the decrease in mass of PIP2; [3H]inositol monophosphate ([3H]IP1) levels demonstrated no differences between the lithium ECS and lithium-alone groups. These results indicate that ECS stimulates the inositol lipid cycle in brain possibly due to neurotransmitter release. Moreover, the effects of lithium suggest other possible sites of action of this cation on inositol lipid metabolism in addition to an inhibition of inositol-1-phosphatase.

Animals↗
PubMed2003

Synthesis of potent Ins(1,4,5)P3 5-phosphatase inhibitors by modification of myo-inositol 1,3,4,6-tetrakisphosphate.

Three myo-inositol tetrakisphosphate analogues were synthesised based upon myo-inositol 1,3,4,6-tetrakisphosphate: 2,5-di-O-methyl myo-inositol-1,3,4,6-tetrakisphosphate 19 and its phosphorothioate derivative 22, together with myo-inositol 1,3,4,6 tetrakisphosphorothioate 25. These compounds were prepared by phosphitylating 2,5-di-O-methyl-myo-inositol and 2,5-di-O-benzyl-myo-inositol followed by oxidation with t-butylhydroperoxide or sulfoxidation at room temperature using sulfur in a mixed solvent of DMF and pyridine. Sulfoxidation was complete within 15 min; however, without DMF, the reaction was much slower, and required overnight. When evaluated against Ins(1,4,5)P(3) 5-phosphatase, 3-kinase and for Ca(2+) release at the Ins(1,4,5)P(3) receptor, only weak activity was observed for Ca(2+) release. 22 and 25 are potent 5-phosphatase inhibitors and 25 is a moderate inhibitor of 3-kinase. Thus, we have synthesised potent enzyme inhibitors, which do not mobilise Ca(2+) and devised conditions for quick, clean and inexpensive sulfoxidation of inositol polyphosphite intermediates.

Binding Sites↗
PubMed2001

Novel synthesis of enantiomerically pure natural inositols and their diastereoisomers.

The various inositol polyphosphates have been found to trigger many important biological processes. Although the knowledge of this phosphoinositide signaling system has been discovered in the past 10 years, many factors remain unclear. For this reason, there is an increased demand for supplies of D-myo-inositol and particularly of novel analogues to investigate these biological mechanisms in more detail. Herein, we report the efficient syntheses of all diastereoisomers of inositol starting with 6-O-acetyl-5-enopyranosides. Conversion of 6-O-acetyl-5-enopyranosides into the corresponding substituted cyclohexanones (Ferrier-II rearrangement) was found to proceed efficiently with a catalytic amount of palladium dichloride. Stereoselective reduction of beta-hydroxy ketones obtained provided the precursors to all inositol diastereoisomers in good to excellent yields and with high stereoselectivities. Good accessibility of these enantiomerically pure inositol diastereoisomers results in the efficient syntheses of D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate.

Inositol↗
PubMed1991

The inositol phosphate/diacylglycerol signalling pathway in Trypanosoma cruzi.

Using [32P]Pi and [3H]inositol as precursors, we have detected the presence of phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate, and their derivatives inositol phosphate, inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate respectively, in Trypanosoma cruzi epimastigotes. Using digitonin-permeabilized cells it was possible to detect a stimulation in the formation of inositol 1,4,5-trisphosphate and inositol 1,4-bisphosphate as well as an increased generation of diacylglycerol in the presence of 1 mM-CaCl2. These results are consistent with the operation of a functional inositol phosphate/diacylglycerol pathway in T. cruzi, and constitute the first demonstration of the presence and activation of this pathway in a parasitic protozoan. These results also indicate that this pathway is conserved during evolution from lower to higher eukaryotic organisms.

Animals↗
PubMed1998

PTB domain of insulin receptor substrate-1 binds inositol compounds.

We examined whether a phosphotyrosine binding (PTB) domain from the human insulin receptor substrate-1 (hIRS-1) is capable of binding inositol phosphates/phosphoinositides. The binding specificity was compared with that of the pleckstrin homology (PH) domain derived from the same protein because the three dimensional structure was found to be very similar to that of the PH domain, despite the lack of sequence similarity. We also attempted to locate the site of binding of the inositol compounds. The PTB domain bound [3H]Ins(1,4, 5)P3, which was displaced most strongly by Ins(1,3,4,5,6)P5 and InsP6, indicating that these inositol polyphosphates show the highest affinity. The PTB domain bound to liposomes containing PtdIns(4,5)P2, PtdIns(3,4,5)P3 and PtdIns(3,4)P2, but not phosphatidylinositol. In contrast, the PH domain showed a preference for Ins(1,4,5)P3, the polar head of PtdIns(4,5)P2. Site-directed mutagenesis studies were performed to map the binding site for inositol phosphates in the PTB domain. Mutation of K169Q, K171Q or K177Q, located in the loop connecting the beta1 and beta2 strands, which is partially responsible for binding inositol phosphates/phosphoinositides in the PH domains of several other proteins, reduced binding activity, probably because of a reduction in affinity. Mutation of R212Q or R227Q, shown to be involved in the binding of a phosphotyrosine, had little effect on the binding capacity. These results indicate that the PTB domain of hIRS-1 can bind inositol phosphates/phosphoinositides. Therefore signalling through the PTB domain could be regulated by the binding not only of proteins with phosphotyrosine but also of inositol phosphates/phosphoinositides, implying that PTB domains could be involved in a myriad of interconnections between intracellular signalling pathways.

Amino Acid Sequence↗
PubMed2002

The phosphatidylinositol signalling system in elongating bovine blastocysts; formation of phosphoinositides, inositol phosphates and stimulation by growth factors.

The uptake of myo-inositol and its incorporation into the phosphoinositides and inositol phosphates of the phosphatidylinositol (PtdIns) signal transduction system by in vivo elongating cattle blastocysts was investigated using [3H]myo-inositol. Uptake was examined in 13-, 14- and 16-day-old blastocysts and was largely sodium-dependent throughout (P<0.001), indicating the presence of a sodium-dependent inositol transporter. Incorporation of inositol into the three phosphoinositides, PtdIns, PtdInsP and PtdInsP2, and the inositol phosphates of the phosphatidylinositol signal transduction system was examined at Days 14 and 16; incorporation into the three phosphoinositides and into the inositol phosphate species, InsP1, InsP2, InsP3 (including the second messenger, Ins(1,4,5)P3) and InsP4 was detected in both blastocyst stages. The effects of the peptide growth factor, epidermal growth factor (EGF), and the lipid growth factors, lysophosphatidic acid (LPA) and platelet activating factor (PAF), on the activity of the phosphatidylinositol signalling system in 14- and 16-day-old blastocysts were examined. All growth factors significantly stimulated phosphatidylinositol signalling activity. Epidermal growth factor was stimulatory (P<0.001) only in 16-day-old blastocysts, whereas LPA and PAF were active in both 14- (P<0.005 for LPA and P<0.001 for PAF) and 16-day-old blastocysts (P<0.001 for LPA and PAF). These results indicate that the phosphatidylinositol signalling system is present in cattle blastocysts at the elongation stage and is responsive to stimulation by growth factors.

Animals↗
PubMed1988

Isolation of 1-monomethylphosphoinositol 4,5-bisphosphate [a product of methanolysis of inositol 1,2-(cyclic)-4,5-trisphosphate] from Swiss mouse 3T3 cells.

We have noted two previously undescribed inositol polyphosphates in neutral methanol extracts from Swiss mouse 3T3 cells that were grown in [3H]inositol and stimulated with platelet-derived growth factor. They have been identified as 1-monomethylphosphoinositol 4,5-bisphosphate and 1-monomethylphosphoinositol 4-phosphate by comparison to a synthesized standard using HPLC chromatography, paper electrophoresis, and enzymatic dephosphorylation with inositol polyphosphate 5-phosphomonoesterase and intestinal alkaline phosphatase [orthophosphoric-monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1]. We propose that these compounds are formed by methanolysis of inositol 1,2-(cyclic)-4,5-trisphosphate and inositol 1,2-(cyclic)-4-bisphosphate present in the cells. Inositol cyclic phosphates did not react with neutral methanol in the absence of the cells, which are required for the methanolysis reaction. These findings suggest a role for inositol cyclic phosphates as reactive compounds that are added to as yet unidentified cellular acceptors.

Animals↗
PubMed1989

Chiral synthesis of D- and L-myo-inositol 1,4,5-trisphosphate.

Chiral inositols (D-chiro-inositol from D-pinitol and L-chiro-inositol from L-quebrachitol) were converted to the 3,4-di-O-benzyl ethers, which were selectively benzoylated to yield the 1,2,5-tri-O-benzoyl-3,4-di-O-benzyl-chiro-inositols. The free hydroxyl group in each derivative was inverted by way of the trifluoromethane sulfonate ester to provide D- and L-1,2,4-tri-O-benzoyl-5,6-di-O-benzyl-myo-inositol. Hydrogenolysis to remove the benzyl ether groups gave the enantiomeric 1,2,4-tri-O-benzoyl-myo-inositols, which were phosphorylated by a dibenzylphosphite triester method. After hydrogenolysis and saponification of the derivatives, the D- and L-myo-inositol 1,4,5-trisphosphates were isolated as the crystalline cyclohexylammonium salts in gram quantity.

Chromatography, High Pressure Liquid↗
PubMed1985

Transmembrane signalling by the T cell antigen receptor. Perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores.

Antibodies against the T3-antigen receptor complex can activate the human T cell line, Jurkat, to produce interleukin 2 (2-5). This activation is initiated by a receptor-mediated increase in the concentration of free cytoplasmic calcium ions [Ca2+]i (3, 4). In this communication, we investigate the mechanism by which the receptor complex increases [Ca2+ )i in Jurkat cells. The initial receptor-mediated change in [Ca2+]i can occur when extracellular Ca2+ is depleted by EGTA. Perturbation of the T cell antigen receptor, therefore, generates a signal which mobilizes Ca2+ from intracellular stores. As inositol trisphosphate appears to function as such a signal for certain hormone receptors, we measured the levels of inositol trisphosphate and of the other inositol phosphate compounds in Jurkat. Antibodies to either the antigen receptor heterodimer or T3 determinants result in marked elevations of all three inositol phosphates. These changes in inositol phosphates are not secondary to the receptor-mediated increases in [Ca2+]i as demonstrated by the inability of the Ca2+ ionophore, ionomycin, to affect the levels of any of these compounds. In concentrations between 0.1 and 1 microM, purified inositol trisphosphate releases Ca2+ from permeabilized Jurkat cells. Taken together, these data indicate that, during activation, perturbation of the T3-antigen receptor complex generates inositol trisphosphate. This compound functions as an intracellular signal to release Ca2+ from intracellular stores, leading to increases in [Ca2+]i.

Aminoquinolines↗
PubMed1988

Neural function: metabolism and actions of inositol metabolites in mammalian brain.

In the nervous system, a variety of cell types respond to external stimuli through the inositol lipid signalling pathways. The stimulus-coupled sequence of intracellular events has been investigated in a homogeneous model system, the cloned mammalian neural cell line NG115-401L. The neural peptide bradykinin stimulates a rapid production of identified inositol phosphate isomers and an intracellular Ca2+ discharge followed by a persistent plasma membrane influx. The temporal sequence suggests that Ins(1,4,5)P3 or Ins(1,3,4,5)P4 or both may coordinate these events in a neuronal cell, as has been suggested in other cell types. Thapsigargin, an irritant and tumour-promoting plant product, produces calcium transients in the absence of inositol phosphate production, and may provide a new tool for investigating the interactions between inositol phosphates and changes in cellular calcium homeostasis. In the 401L line, high levels of radiolabelled InsP5 and InsP6 have been detected, which has led to the evaluation of their possible occurrence and actions in normal brain. Both InsP5 and InsP6 are produced from a radiolabelled myo-inositol precursor in intact mature brain in a region-specific manner. This suggests that both inositol polyphosphates may be end products of regionally regulated biosynthetic pathways. When microinjected into a nucleus of the brainstem, or iontophoretically applied to the dorsal horn of the spinal cord, both InsP5 and InsP6, but not Ins(1,3,4,5)P4 isomers, appear to be potent neural stimulants. These results suggest that the inositol lipid signalling pathways may generate both intracellular and extracellular signals in brain.

Animals↗
PubMed1985

Activation of muscarinic and of alpha 1-adrenergic receptors on astrocytes results in the accumulation of inositol phosphates.

Astrocyte-enriched cultures prepared from the newborn rat cortex incorporated [3H]myo-inositol into intracellular free inositol and inositol lipid pools. Noradrenaline and carbachol stimulated the turnover of these pools resulting in an increased accumulation of intracellular [3H]inositol phosphates. The effects of noradrenaline and carbachol were dose-dependent and blocked by specific alpha 1-adrenergic and muscarinic cholinergic receptor antagonists, respectively. The increase in [3H]inositol phosphate accumulation caused by these receptor antagonists was virtually unchanged when cultures were incubated in Ca2+-free medium, but was abolished when EGTA was also present in the Ca2+-free medium. Cultures of meningeal fibroblasts, the major cell type contaminating the astrocyte cultures, also accumulated [3H]myo-inositol, but no increased accumulation of [3H]inositol phosphates was found in response to either noradrenaline or carbachol.

Animals↗
PubMed1987

Stimulation of inositol phosphate production by neurotensin in neuroblastoma N1E115 cells: implication of GTP-binding proteins and relationship with the cyclic GMP response.

The association of neurotensin to its receptor in differentiated neuroblastoma N1E115 cells led to a fast and transitory increase of the intracellular concentration in inositol triphosphate and inositol biphosphate, followed by a slower and more stable increase inositol monophosphate. The action of inositol 1,4,5-triphosphate on digitonin-permeabilized N1E115 cells resulted in a stimulation of cyclic GMP levels that mimicked that induced by neurotensin. Therefore, the cyclic GMP stimulation is probably a consequence of the initial inositol triphosphate formation triggered by neurotensin. Fluoroaluminate ions and pertussis toxin had the capacity to modulate positively and negatively, respectively, the formation of inositol triphosphate induced by neurotensin, indicating that GTP-binding proteins are involved in the regulation of inositol phosphate levels by neurotensin receptors.

Aluminum↗
PubMed1988

Stimulation of inositol incorporation into lipids of PC12 cells by nerve growth factor and bradykinin.

The effects of bradykinin (BK) and lithium on the phosphatidylinositol cycle were examined in PC12 cells cultured for 20 h in the presence [PC12(+)] or in the absence [PC12(-)] of nerve growth factor (NGF). BK (1 microM) induced a small stimulation of the incorporation of myo-[2-3H]inositol into the lipids of PC12(-) cells and a three- to fourfold stimulation of such incorporation into the lipids of PC12 (+) cells. About 15 h of incubation with NGF and greater than 10 min of incubation with BK were needed for maximal stimulation of inositol incorporation by BK. In the presence of 25 mM LiCl, BK stimulated the inositol monophosphate levels nine-fold in PC12 (-) and 30-fold in PC12 (+) cells. After incubation for 20 h with NGF, an increased binding of [3H]BK to the PC12 (+) cells was observed at 4 degrees C. Exposure of the cells for 30 min to 25 mM LiCl enhanced the effect of BK on the inositol incorporation into total inositol lipids, especially in PC12(+) cells. In these cells, LiCl in the presence of BK also increased several-fold the intracellular levels of inositol bisphosphate and inositol trisphosphate.

Adrenal Gland Neoplasms↗
PubMed1989

Subacute and chronic in vivo lithium treatment inhibits agonist- and sodium fluoride-stimulated inositol phosphate production in rat cortex.

We have investigated the effects of in vivo lithium treatment on cerebral inositol phospholipid metabolism. Twice-daily treatment of rats with LiCl (3 mEq/kg) for 3 or 16 days resulted in a 25-40% reduction in agonist-stimulated inositol phosphate production, compared with NaCl-treated controls, in cortical slices prelabelled with [3H]inositol. A small effect was also seen with 5-hydroxytryptamine (5-HT) 24 h after a single dose of LiCl (10 mEq/kg). Dose-response curves to carbachol and 5-HT showed that lithium treatment reduced the maximal agonist response without altering the EC50 value. This inhibition was not affected by the concentration of LiCl in the assay buffer. Stimulation of inositol phosphate formation by 10 mM NaF in membranes prepared from cortex of 3-day lithium-treated rats was also inhibited, by 35% compared with NaCl-treated controls. Lithium treatment did not alter the kinetic profile of inositol polyphosphate formation in cortical slices stimulated with carbachol. Muscarinic cholinergic and 5-HT2 bindings were unaltered by lithium, as was cortical phospholipase C activity and isoproterenol-stimulated cyclic AMP formation. [3H]Inositol labelling of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by 3-day lithium treatment. The results, therefore, indicate that subacute or chronic in vivo lithium treatment reduces agonist-stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G-protein-phospholipase C coupling.

Animals↗
PubMed1991

A method to measure simultaneously cyclic AMP and inositol phosphate accumulation in rat brain slices.

The simultaneous measurement of the accumulation of cyclic AMP and inositol phosphates in rat cerebral cortical slices is described. After stimulation, the separation of cyclic AMP and inositol phosphates was achieved using ion-exchange chromatography and their concentrations were determined by means of a double-labeling technique, the substrates adenine and inositol being labeled with 14C and 3H, respectively. The recoveries were 70-80% for inositol phosphates and 40-50% for cyclic AMP. To test the applicability of the method, norepinephrine was chosen as an agonist, because it is known to stimulate the production of these two second messengers by interacting with alpha- and beta-adrenergic receptors. This procedure is an improvement over existing methods, because we obtained the simultaneous formation of 3H-inositol phosphates and [14C]cyclic AMP in a concentration-dependent process. EC50 values were similar for the two, 8.5 +/- 3.9 microM for 3H-inositol phosphates and 20.2 +/- 6.3 microM for [14C]cyclic AMP, and close to the values obtained when each process was studied alone. The action of adrenergic antagonists was also tested. Propranolol blocked the norepinephrine stimulation of [14C]cyclic AMP, but did not inhibit the norepinephrine stimulation of 3H-inositol phosphates. The opposite results were observed with prazosin. Our results suggest that this method could be a useful tool to examine the interaction between these two receptor-coupled effectors.

1-Methyl-3-isobutylxanthine↗
PubMed2003

Inositol and phosphate regulate GIT1 transcription and glycerophosphoinositol incorporation in Saccharomyces cerevisiae.

Glycerophosphoinositol is produced through deacylation of the essential phospholipid phosphatidylinositol. In Saccharomyces cerevisiae, the glycerophosphoinositol produced is excreted from the cell but is recycled for phosphatidylinositol synthesis when inositol is limiting. To be recycled, glycerophosphoinositol enters the cell through the permease encoded by GIT1. The transport of exogenous glycerophosphoinositol through Git1p is sufficiently robust to support the growth of an inositol auxotroph (ino1Delta). We now report that S. cerevisiae also uses exogenous phosphatidylinositol as an inositol source. Evidence suggests that phosphatidylinositol is deacylated to glycerophosphoinositol extracellularly before being transported across the plasma membrane by Git1p. A genetic screen identified Pho86p, which is required for targeting of the major phosphate transporter (Pho84p) to the plasma membrane, as affecting the utilization of phosphatidylinositol and glycerophosphoinositol. Deletion of PHO86 in an ino1Delta strain resulted in faster growth when either phosphatidylinositol or glycerophosphoinositol was supplied as the sole inositol source. The incorporation of radiolabeled glycerophosphoinositol into an ino1Delta pho86Delta mutant was higher than that into wild-type, ino1Delta, and pho86Delta strains. All strains accumulated the most GIT1 transcript when incubated in media limited for inositol and phosphate in combination. However, the ino1Delta pho86Delta mutant accumulated approximately threefold more GIT1 transcript than did the other strains when incubated in inositol-free media containing either high or low concentrations of P(i). Deletion of PHO4 abolished GIT1 transcription in a wild-type strain. These results indicate that the transport of glycerophosphoinositol by Git1p is regulated by factors affecting both inositol and phosphate availabilities and suggest a regulatory connection between phosphate metabolism and phospholipid metabolism.

Carrier Proteins↗
PubMed1988

High calcium and other divalent cations increase inositol trisphosphate in bovine parathyroid cells.

Calcium and other divalent cations rapidly increase intracellular free Ca2+ ([Ca2+]i) in bovine parathyroid cells and inhibit PTH release. In other secretory cells, agonist-dependent generation of inositol trisphosphate (InsP3) through polyphosphoinositide turnover initiates the rise in [Ca2+]i by mobilizing Ca2+ from intracellular stores. To determine whether polyphosphoinositide breakdown is involved in mediating the response to Ca2+ and the divalent cations Ba2+, Mn2+, and Sr2+, we measured the production of inositol polyphosphates in parathyroid cells. Within 120 sec of increasing extracellular Ca2+ to 2.0 mM, InsP3, inositol bisphosphate (InsP2), and inositol monophosphate (InsP1) rose 95 +/- 37%, 87 +/- 17%, and 96 +/- 29%, respectively, vs. values in cells at 0.5 mM Ca2+ (n = 5). Raising extracellular Ca2+ from 0.5-3.0 mM produced even greater peak increments of 134 +/- 13%, 179 +/- 35%, and 313 +/- 65% in InsP3, InsP2, and InsP1, respectively, by 120 sec (n = 4). Similarly, within 10 sec of their addition, BaCl2 (2 mM), MnCl2 (2 mM), and SrCl2 (4 mM) stimulated the production of InsP3 56 +/- 2%, 152 +/- 31%, and 160 +/- 25%, respectively, vs. that in untreated cells at 0.5 mM Ca2+. At later time points, InsP2 and InsP1 were increased. The Ca2+ ionophore ionomycin at concentrations up to 500 nM had no effect on inositol phosphates, although it inhibited PTH release in a dose-dependent manner. Since high Ca2+ and other divalent cations depolarize parathyroid cells, we assessed the effect of high extracellular K+ on inositol polyphosphates. The addition of depolarizing concentrations of K+ (40 mM) did not change inositol phosphates. Thus, Ca2+ and other divalent cations increase the production of InsP3, InsP2, and InsP1 in parathyroid cells by a mechanism independent of increases in [Ca2+]i and of membrane depolarization. We conclude that parathyroid cells express membrane receptors or sensors for Ca2+ and other divalent cations linked to polyphosphoinositide turnover.

Animals↗
PubMed1990

Thyrotropin-induced elevation of 1,2-diacylglycerol and stimulation of growth of FRTL-5 cells are not dependent on inositol lipid hydrolysis.

We reported that TSH, which stimulates cAMP accumulation and proliferation of FRTL-5 thyroid cells, chronically increases the 1,2-diacylglycerol (1,2-DG) content of FRTL-5 cells. Because activation of inositol lipid hydrolysis by a phospholipase-C enzyme would generate 1,2-DG, we compared the effects of TSH on inositol lipid metabolism to TSH-induced increases in 1,2-DG content and stimulation of cAMP accumulation and cell growth. Acute stimulation of inositol lipid hydrolysis did not occur with doses of 1000 microU/ml or lower, but did occur with TSH doses of 3000 microU/ml and higher, with rates between 1-4%/h. More importantly, in cells chronically exposed to TSH, the rate of inositol lipid hydrolysis was increased only at TSH doses of 10,000 microU/ml or greater, and the maximum rate was 4-5%/h. When cells were growth arrested by TSH deprivation, there was no change in the content of inositol phosphates or polyphosphoinositides. In contrast to the high doses of TSH required to stimulate inositol lipid hydrolysis, TSH-induced elevation of 1,2-DG content and stimulation of cAMP accumulation and growth occurred at physiological TSH concentrations, with minimal effective doses in the range of 1-10 microU TSH/ml, and half-maximally effective doses between 50-200 microU TSH/ml. These data suggest that inositol lipid hydrolysis does not mediate the proliferative response to TSH in FRTL-5 cells and is not the mechanism by which increases in 1,2-DG content occur at physiological TSH concentrations.

Animals↗