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PubMed1989

Pulmonary alveolar macrophages express a polyamine transport system.

Polyamine transport is an important mechanism by which cells regulate their intracellular polyamine content. It is well established that the lung has a high capacity for polyamine transport, and recently the polyamine putrescine has been shown to be selectively accumulated into the type II pneumocyte of rabbit lung slices (Saunders et al.: Lab. Invest., 95:380-386, 1988). In addition, it has been suggested that there may be more than one polyamine transport system in lung tissue (Byers et al.: Am. J. Physiol., 252:C663-C669, 1987). In the present study, we have examined whether there are differences in the distribution of putrescine and spermidine uptake activities in isolated rabbit lung cells. We report that pulmonary alveolar macrophages have a greater rate of uptake of both putrescine and spermidine than the total lung cell population. Kinetic analysis of the polyamine uptake system present in macrophages showed putrescine uptake consisted of a saturable (Km = 2.1 microM) and nonsaturable component whilst spermidine uptake consisted of both a high- and a low-capacity saturable component (Km = 0.16 microM and 1.97 microM, respectively). The rate of polyamine transport was similar to those reported for many proliferative or tumor cell-lines and appears to be greater than any other major lung cell type. Inhibition studies of the transport of polyamines into pulmonary alveolar macrophages suggested that the uptake of both putrescine and spermidine was mediated by the same system, which could not be described by simple Michaelis-Menten kinetics. The transport appears to be reversible due to significant efflux. This is the first study to describe the presence of multiple polyamine transport systems in pulmonary alveolar macrophages.

Animals↗
PubMed1995

The inter-relationship between polyamines and the L-arginine nitric oxide pathway in the human placenta.

Nitric oxide (NO) and polyamines are both products of L-arginine metabolism. In placental villous tissue NO and polyamines have been shown to be synthesized although the physiological significance is not known. We have measured polyamine (putrescine, spermidine and spermine) concentrations and nitric oxide synthase activities (NOS) in first trimester and term placentae from normal and abnormal pregnancies, but no difference was observed in polyamine concentrations between normal term and placentae from growth-retarded and pre-eclamptic pregnancies. Significantly higher levels of polyamines were found in first trimester when compared to normal term placentae and there was a significant correlation between NOS activity and the cellular polyamine levels. Cultures of a trophoblast cell line, BeWo, have been used to study the interaction of added polyamines on NOS activity. Although there was a general tendency for all the polyamines to inhibit NOS activity only putrescine was able to significantly inhibit NO production by these cells. It is thought that the L-arginine-NO-polyamine pathway may have a physiological role during pregnancy.

Amino Acid Oxidoreductases↗
PubMed1997

Polyamine regulatory processes and oxidative stress in monocrotaline-treated pulmonary artery endothelial cells.

Alterations in polyamine metabolism may be a critical mechanism of monocrotaline (MCT)-induced structural remodeling of the pulmonary vasculature. In the present study, the hypothesis that MCT, through the induction of oxidative stress, modulates cellular polyamine regulatory mechanisms which in turn might be involved in the upregulation of fibronectin production in pulmonary artery endothelial cells (PAEC) was examined. A 24-h treatment with MCT significantly increased PAEC polyamine concentrations as compared to vehicle-treated cells. In addition, exposure to MCT caused an increase in abundance of ornithine decarboxylase (ODC) mRNA, upregulation of ODC activity and enhancement of spermidine import into PAEC. Inhibition of de novo polyamine synthesis further increased spermidine uptake in MCT-treated cells. The depletion of cellular polyamine contents through the blockade of both de novo polyamine biosynthesis and polyamine transport prevented MCT-induced increases in the medium level of fibronectin. In addition, PAEC treatment with MCT stimulated cellular oxidative stress as determined by increased levels of thiobarbituric acid reactive substances, enhanced dichlorofluorescein fluorescence and activation of NF-kappa B. A co-treatment with dimethylthiourea, an oxygen radical scavenger, prevented MCT-induced increases in cellular oxidation and attenuated disturbances in polyamine metabolism. These data suggest that MCT can stimulate polyamine regulatory processes in PAEC possibly through an increase in cellular oxidative stress. The present study may have significant implication in understanding mechanisms of MCT-induced pulmonary hypertension and remodeling of pulmonary vasculature.

Animals↗
PubMed2002

Polyamine depletion induces apoptosis through mitochondria-mediated pathway.

Polyamines, namely putrescine, spermidine, and spermine, are essential for cell survival and proliferation. A decrease in intracellular polyamine levels is associated with apoptosis. In this study, we used inhibitors of polyamine biosynthesis to examine the effect of polyamine depletion. A combination of inhibitors of ornithine decarboxylase, S-adenosylmethionine decarboxylase, or spermidine synthase decreased intracellular polyamine levels and induced cell death in a WEHI231 murine B cell line. These cells exhibited apoptotic features including chromatin condensation and oligonucleosomal DNA fragmentation. Addition of exogenous polyamines reversed the observed features of apoptotic cell death. Similar effects were also observed in other cell lines: a human B cell line Ramos and a human T cell line Jurkat. Depletion of polyamines induced activation of caspase-3 and disruption of the mitochondrial membrane potential (Delta psi m). Inhibition of caspase activities by an inhibitor prevented the apoptotic nuclear changes but not Delta psi m disruption induced by polyamine depletion. Overexpression of Bcl-xl, an anti-apoptotic Bcl-2 family protein, completely inhibited Delta psi m disruption, caspase activation, and cell death. These results indicate that the depletion of intracellular polyamines triggers the mitochondria-mediated pathway for apoptosis, resulting in caspase activation and apoptotic cell death.

Adenosylmethionine Decarboxylase↗
PubMed1988

Regulation of protein synthesis by polyamines.

Present experimental data show that the synthesis of ribosomal protein S1 and PI protein was stimulated greatly by polyamines at the early stage after addition of putrescine in polyamine-requiring mutants of E. coli. No macromolecular synthesis was stimulated at this stage. Polyamine stimulation of the synthesis of these proteins probably plays an important role for cell growth. In polyamine-deficient bovine lymphocytes, protein synthesis became perturbed before RNA and DNA synthesis. Among enzymes concerned with DNA replication, thymidine kinase activity was most strongly influenced by polyamines. The activity in polyamine-deficient cells was only 7% of the level in normal cells. Judging from the amount of thymidine kinase mRNA and its distribution in polysomes, it was concluded that polyamines mainly regulate the synthesis of thymidine kinase at the level of initiation of protein synthesis. A polyamine-free protein synthetic system, established from components of rabbit reticulocytes, consisted of globin mRNA, salt-washed ribosomes, partially purified initiation factors, and pH 5 enzymes. Spermidine added to this system not only lowered the optimal magnesium concentration required for globin synthesis, but it also stimulated the globin synthesis 8- to 10-fold. The optimal spermidine concentration was 0.4 to 0.6 mM, a concentration similar to that in intact rabbit reticulocytes. The ratio of alpha to beta globin chains synthesized in the presence of spermidine and Mg2+ was approximately 1.0, while the ratio in the presence of only Mg2+ was approximately 1.5. The results strongly suggest that polyamines play an important role in rabbit reticulocyte protein synthesis.

Animals↗
PubMed1994

Estradiol control of ornithine decarboxylase mRNA, enzyme activity, and polyamine levels in MCF-7 breast cancer cells: therapeutic implications.

Previous studies have shown that natural polyamines-putrescine, spermidine, and spermine-play a key role in the mechanism of action of estrogens in breast cancer. Ornithine decarboxylase (ODC) is the first enzyme of the polyamine biosynthetic pathway. To examine estrogenic regulation of polyamine biosynthesis in breast cancer, we measured ODC mRNA, ODC activity, and polyamine levels in G1 synchronized MCF-7 cells. ODC mRNA and activity increased four-fold over that of cells in G1 phase between 8 to 16 h after the addition of estradiol. Polyamine levels showed a sharp increase by 8 h after the addition of estradiol and decreased by 12 h. We further examined whether synthetic homologs of putrescine or spermidine could replace natural polyamines in supporting MCF-7 cell growth. Treatment of MCF-7 cells with 1 mM difluoromethylornithine (DFMO), an inhibitor of ODC, suppressed putrescine, spermidine, and spermine levels by 74, 78, and 10%, respectively, within 48 h. Cells treated with DFMO for 48 h were supplemented with either putrescine or its homologs or spermidine or its homologs. Diaminopropane, diaminobutane (putrescine), and diaminopentane were capable of fully or partially reversing the growth inhibitory effects of DFMO, whereas diaminoethane had no significant effect. Among a series of triamines, H2N(CH2)nNH(CH2)3NH2 (where n = 2 to 8; abbreviated as APn n = 4 for spermidine, or AP4), spermidine was most effective in reversing the effects of DFMO, whereas compounds with shorter or longer methylene bridging regions were less effective. AP8 was ineffective in reversing the growth inhibitory effects of DFMO. At 10 microM concentration, AP8 also inhibited DNA synthesis by 66%, as measured by [3H]-thymidine incorporation. These data show that MCF-7 cells have a strong requirement for polyamines for their growth and that estradiol stimulates the polyamine cascade by inducing the ODC mRNA level. Our results also suggest that polyamine homologs such as AP8 might be potentially useful in breast cancer therapy.

Breast Neoplasms↗
PubMed1995

Polyamines in brain tumor therapy.

In the search for ways to augment current brain tumor therapies many have sought to exploit the fact that adult brain tissue is virtually lacking in cell division. This endorses a special appeal to therapeutic approaches which target the dependence on cell division for brain tumor growth. Polyamines play an essential role in the proliferation of mammalian cells and depletion results in inhibition of growth. As a result, there are investigations into the feasibility of controlling tumor growth by targeting the enzymes in polyamine metabolism with specific enzyme inhibitors. DFMO, an inhibitor of putrescine synthesis, is a cytostatic agent which in combination with tritiated radioemitters or cytotoxic agents such as, MGBG or BCNU is an effective antitumor agent, but the effectiveness of DFMO in vivo is reduced by tumor cell uptake of polyamines released into the circulation by normal cells and from gut flora or dietary sources. However, DFMO therapy combined with elimination of exogenous polyamines inhibits tumor growth but also results in body weight loss, reduced protein synthesis and evidence of toxicity. Furthermore, tumor growth recurs upon termination of treatment. In contrast, competitive polyamine analogs function in the homeostatic regulation of polyamine synthesis but fail to fulfill the requirements for growth and they continue to inhibit tumor growth for several weeks after cessation of treatment. Analogs are now in clinical trials. However, their action may be highly specific and differ from one cell type to another. We suggest that the effectiveness of polyamine based therapy would be enhanced by two approaches: local delivery by intracerebral microdialysis and tumor cell killing by internal radioemitters such as tritiated putrescine or tritiated thymidine which are taken up in increased amounts by polyamine depleted tumor cells. The growth inhibition by polyamine depletion prevents the dilution of the radioactive putrescine and thymidine. The overload of radioactivity kills the growth inhibited cells so that growth cannot recur when treatment terminates.

Adult↗
PubMedDate not supplied

Accumulation of exogenous polyamines in gerbil brain after ischemia.

Regionally selective delayed neuronal degeneration is a characteristic sequel of cerebral ischemia. Recent evidence indicates that changes in brain polyamine metabolism may be critical for nerve cell survival after ischemia. Within hours after ischemia, intracellular putrescine levels are greatly increased and remain elevated for days, whereas only minor changes are noted in the levels of the polyamines spermine and spermidine. In contrast, the extracellular levels of all polyamines are low after ischemia. Injections of polyamines following ischemia, however, can protect neurons in the gerbil brain from delayed cell death, with spermine being the most potent of the polyamines. In the present study, therefore, we sought to determine if increased polyamine uptake occurs in the brain after ischemia. In the hippocampal slice preparation, temperature-dependent uptake was unique for spermine, but not for spermidine or putrescine. Uptake of [14C]spermine was transiently increased after ischemia, peaking at 150% of control by 12-13 h and subsiding by 24 h. Intravenous injections of [3H]spermidine resulted in a postischemic accumulation of this polyamine throughout the forebrain parenchyma. We conclude that: 1. Active cellular uptake of spermine is transiently increased early after ischemia; 2. A nonspecific accumulation of exogenous polyamines occurs early after ischemia probably owing to a compromised blood-brain barrier, and 3. The findings indicate that exogenous polyamines can exert their effect directly in the brain after ischemia.

Animals↗
PubMed1999

Polyamine system in developing rat eye and an animal model of retinopathy of prematurity.

BACKGROUND: In experimental models of retinopathy of prematurity (ROP), a vasoproliferative disorder of the retina, retinal lesions are usually assessed by morphological examination. However, studies suggest that the polyamine system may be useful in monitoring proliferation processes. For this reason, polyamine concentrations in rat erythrocytes (RBC) and the regulation of polyamine system in rat eyes under the conditions relevant to ROP were investigated. METHODS: Newborn Wistar rats were reared in room air (control) or exposed first to hyperoxia (60% or 80% oxygen, 2 weeks) and then to normoxia (relative hypoxia, 1 or 2 weeks). Blood was collected from orbital vessels at 2 weeks of age and before death. Polyamine system-related enzyme activities were measured in retina and lens with radioassays. Polyamines were quantified by fluorometry after extraction, dansylation and HPLC separation. RESULTS: Oxygen (80% only) significantly decreased RBC polyamine concentrations, which then markedly increased after rats were transferred for a week to normal air, suggesting retardation of growth processes and compensatory stimulation, respectively. However, polyamine system changes in the rat eye were not so pronounced. Enzyme activities and polyamine concentrations tended to be lower in retina after hyperoxia and were only slightly higher, with the exception of ornithine decarboxylase, after a subsequent 1 week of normoxia. In litters subjected to normoxia for longer periods no changes were found. CONCLUSION: The transient and short-lived alteration in polyamine metabolism, especially in the eye, suggests that exposure of newborn rats to high oxygen supplementation followed by normoxia does not necessarily result in marked retinopathy.

Aging↗
PubMed1984

Polyamines stimulate D-glucose transport in isolated renal brush-border membrane vesicles.

Polyamines are natural constituents of most living organisms. However, their function in normal or pathological conditions is not fully understood. We have investigated in vitro effects of polyamines on characteristic properties of isolated renal brush-border membrane vesicles in order to determine whether polyamines have a regulatory role in membrane transport processes. The polyamines putrescine, spermidine and spermine were found to stimulate D-glucose uptake. Diffusional L-glucose uptake was not altered, indicating that the polyamines affected the active transport of D-glucose, rather than inducing nonspecific changes in membrane lipid properties. The amiloride-sensitive Na+ /H + exchange was slightly inhibited by polyamines while Mg2+ -ATPase activity was stimulated. The polyamine effects could not be explained solely by the polycationic properties of these agents, since polycationic polypeptides had an opposite effect. For example, lysozyme was found to inhibit D-glucose transport. Spermine was incorporated into the trichloroacetic acid-insoluble fraction of brush-border membrane proteins. Results indicated that this incorporation process consisted of at least two components: a Ca2+ -independent component and a Ca2+ -dependent component, possibly as a result of transglutaminase activity which was present in the isolated renal brush-border membranes. By using SDS-polyacrylamide gel electrophoresis in conjunction with fluorography, [3H]spermine was shown to be incorporated into several brush-border membrane proteins, mainly the 57 kDa, 74 kDa, 100 kDa, a heavy molecular weight band (greater than 200 kDa) and a low molecular weight band (less than 10 kDa). Our results suggest that the polyamine effects on membrane function may be due to a covalent modification of membrane proteins, possibly via a transglutaminase-mediated incorporation of polyamines or to the crosslinking of membrane proteins.

Adenosine Triphosphatases↗
PubMed1994

Effect of polyamines on glutamate dehydrogenase within permeabilized kidney-cortex mitochondria and isolated renal tubules of rabbit.

The effect of polyamines on glutamate dehydrogenase [L-glutamate: NAD(P) oxidoreductase (deaminating) [EC 1.4.1.3]) activity has been studied in both permeabilized kidney-cortex mitochondria and isolated renal tubules of rabbit. Spermidine was the most potent inhibitor of glutamate synthesis in permeabilized mitochondria resulting in about 80% decrease of the enzyme activity at 5 mM concentration. Putrescine, alpha-monofluoromethylputrescine (MFMP) and (R,R)-delta-methyl-alpha-acetylenic-putrescine (MAP) were more efficient than spermine. The inhibitory action of polyamines was potentiated by an elevated NADH content in the reaction mixture. Increasing concentrations of either NH4Cl, KCl or NaCl in the incubation medium resulted in a decrease of polyamine-induced inhibition of the enzyme activity, indicating that monovalent cations can compete with polyamines for the binding site at glutamate dehydrogenase. The inhibitory action of spermidine on glutamate synthesis was abolished by 2 mM ADP or 10 mM L-leucine, allosteric activators of the enzyme, as well as on the addition of either oxalate or sulphate at 20 mM concentrations. Spermidine did not affect glutamate formation when NADH was substituted by NADPH, suggesting an importance of the NADH binding to the inhibitory site of the enzyme for a decrease of reductive amination of 2-oxoglutarate by polyamine. Although spermidine did not influence glutamate deamination in the presence of NAD+, it stimulated this process by about 70% when NAD+ was substituted by NADP+. In the presence of ADP the stimulatory effect of polyamine was not significant. The data indicate that in permeabilized rabbit kidney-cortex mitochondria the effect of polyamines on both glutamate formation and glutamate deamination via the reaction catalysed by glutamate dehydrogenase is dependent upon the coenzyme utilized by the enzyme. In the presence of NADH their inhibitory effect on the glutamate formation may be alleviated by allosteric activators of the enzyme, and concentrations of potassium, sodium, sulphate and oxalate. In isolated rabbit renal tubules incubated with 5 mM methionine sulfoximine and aminooxyacetate, in order to inhibit glutamine synthetase and aminotransferases, respectively, 5 mM spermidine decreased glutamate formation by about 30%, while putrescine and spermine did not significantly diminish the enzyme activity. In the presence of octanoate glutamate formation was reduced by about 30% by naturally occurring polyamines as well as MFMP and MAP, indicating that under these conditions NADH rather than NADPH is utilized as the coenzyme. In view of these data it is possible to suggest that polyamines may be of importance to control glutamate dehydrogenase activity under physiological conditions.

Animals↗
PubMed1987

Intracellular polyamine biosynthesis is required for interleukin 2 responsiveness during lymphocyte mitogenesis.

The objective of the present investigation was to define a more precise role for intracellular polyamine biosynthesis with respect to specific inducible events which regulate lymphocyte mitogenesis. In this regard, we have examined the effect of polyamine depletion on interleukin 2 (IL-2) production, receptor expression, and responsiveness in Con A stimulated mononuclear leukocytes (MNL). Polyamine depletion was achieved utilizing the specific irreversible inhibitor of ornithine decarboxylase (ODC), DL-alpha-difluoromethylornithine (DFMO). Polyamine depletion of MNL augmented detectable levels of Con A-induced IL-2 activity. In contrast, the ability of polyamine depleted MNL to respond to saturating levels of IL-2 (100 U/ml) following 72 or 96 hr of Con A stimulation was reduced 100 and 81%, respectively. Nonetheless, polyamine depletion did not impair the induction of IL-2 receptor expression. High-affinity IL-2 receptor density in the polyamine depleted population was greater than control cells late in culture (96 hr). The expression of high-affinity IL-2 receptors did not correlate with an ability to respond to IL-2 in the polyamine depleted population. The results of this study demonstrate for the first time that intracellular polyamine biosynthesis is required for IL-2 responsiveness during a primary mitogenic lymphocyte response.

Concanavalin A↗
PubMed1990

The regulation of G0-S transition in mouse T lymphocytes by polyamines.

While the role of polyamines in DNA synthesis during the S phase of the cell cycle has been repeatedly postulated, recent studies point also to polyamine involvement in the early phase of the G0-S transition. In order to determine polyamine-dependent steps in the cell cycle we have studied the effects of inhibitors of polyamine biosynthesis and exogenous polyamines on the proliferation of T lymphocytes as well as on the expression of some growth-regulated genes. The ability of Con A-stimulated mouse T lymphocytes to enter DNA synthesis was markedly inhibited by methylglyoxal bis(guanylhydrazone) in a dose-dependent manner. This inhibitory effect was stronger in the presence of fetal calf serum containing a high level of activities of polyamine oxidases than in the presence of horse serum. Putrescine and spermine added to T splenocyte culture instead of mitogen-Con A stimulated [3H]thymidine incorporation with kinetics similar to that observed with Con A. The growth-stimulating effects of polyamines were concentration-dependent. Polyamines at optimal growth-stimulating concentrations (10 microM spermine and 80 microM putrescine) induced the expression of genes encoding the cytoskeletal proteins beta-actin, vimentin, and alpha-tubulin to an extent and with kinetics similar to those of Con A. The results presented herein suggest that polyamines are capable of stimulating the transition of G0 cells to the S phase and that this effect may be mediated by their influence on the gene expression.

Animals↗
PubMed1991

Polyamines and the calcium paradox in rat hearts.

Polyamine levels were measured by means of high-performance liquid chromatography in Langendorff-perfused rat hearts subjected to the calcium paradox protocol. The concentrations of putrescine, spermidine and spermine did not change significantly during calcium-free perfusion but decreased when calcium was readmitted. This decrease was due to membrane disruption and release of the polyamines into the coronary effluent. The sum of released and remaining spermidine exceeded the concentration of spermidine in control hearts, but, for spermine, this sum was lower than the control level. The addition of 0.5 mM EGTA to the calcium-free solution raised the myocardial concentrations of putrescine and spermidine and enhanced the net increase of spermidine on calcium repletion. DL-alpha-Difluoromethylornithine (DFMO) inhibited these increases and lowered the putrescine level during all perfusion stages. External polyamines had a negative inotropic effect and inhibited the loss of myoglobin on calcium repletion (order of effectiveness: spermine greater than spermine greater than putrescine). Inhibition of contractions by the combined action of verapamil and ryanodine or by potassium depolarization did not prevent myoglobin loss. External polyamines had no effect on high K/low Na contractures, which were mediated mainly by Na-Ca exchange. Calcium-free perfusion in the presence of 0.5 to 1 mM EGTA improved the membrane protection by polyamines or by diamines and analogues, like ornithine, 1,3-diaminopropane, or DFMO, which, in the absence of EGTA, gave no clear protection. It is concluded that calcium depletion and repletion influences myocardiaal polyamine concentrations by (1) membrane disruption and release of polyamines into the coronary effluent, and (2) probably by a stimulation of ornithine decarboxylase activity. The changes in polyamine concentrations do not seem to have any causal role in calcium overload and cell death. Exogenous polyamines protect against membrane damage.

Animals↗
PubMed1984

Polyamines in mammalian ageing: an oncological problem, too? A review.

This review surveys the literature about changes in polyamine contents and levels of activity of the enzymes involved in the polyamine biosynthetic pathway in organs of ageing mammals. The literature about changes in the polyamine levels in physiological fluids in healthy ageing humans is also reviewed. Generally speaking, decreases in the levels of the main polyamines (noticeably putrescine and spermidine) are observed in different mammalian organs with ageing. The polyamine levels in serum and in urine of healthy human beings are also age-related, declining progressively with increasing age. Some major enzymes (i.e., ornithine decarboxylase (EC 4.1.1.17) and S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) involved in the polyamine biosynthetic pathway show similar trends. Hormonal induction of ornithine decarboxylase activity is strongly reduced in organs of aged animals, as it is in neoplastic organs. There is also some evidence for an age-related decrease in the level of ornithine decarboxylase and its inducibility in mammalian cells cultured in vitro. Some in vitro effects of spermidine and spermine on aged structures or systems are briefly summarized. There is no evidence yet that this generally reduced capacity of mammalian aged organs for polyamine biosynthesis is one of the factors responsible for the well known high incidence of some neoplasias in elderly humans. In view of the typical stimulatory effects of the tumour promoters on polyamine biosynthesis in target tissues and the effects of senescence on the same metabolic pathway, it can be excluded that the ageing process has a tumour promoting effect by itself. However, although the exact mechanism responsible for the increased occurrence of some tumors during mammalian senescence is still obscure, there are enough experimental data (both in humans and in animals) to indicate that the reduced polyamine biosynthetic capacity of aged mammals can account for the slower course of some tumors in elderly patients.

Adenosylmethionine Decarboxylase↗
PubMed1986

Mechanisms and significance of polyamine stimulation of various protein kinase reactions.

An overview of the work on polyamine effects on certain protein kinase reactions is presented. In general, the reactions catalyzed by the messenger-independent protein kinases but not by cyclic nucleotide-, Ca2+-, Ca2+-calmodulin-, and Ca2+-anionic lipid-dependent protein kinases, are markedly enhanced by polyamines. The extent of this stimulation depends critically on the nature of the protein substrate and several other factors. A variety of other polycationic compounds including Co3+(NH3)6, polybrene, and certain aminoglycoside antibiotics exert polyamine-like effects in the same reactions. These observations suggest that the charge properties rather than any strict chemical structure play a role in the action of polyamines. Available data do not support a specific "cofactor" function of these amines for the protein kinases involved in the polyamine-stimulable reactions. It appears that the action of polyamines is mediated via their influence on the conformational status of the protein substrates thereby altering the availability of the phosphorylatable sites to the active sites on the protein kinases. Although this notion is supported by several lines of evidence, at present a role of the influence of polyamines on both the substrate and enzyme cannot be ruled out. Possible physiological relevance of the polyamine-stimulable protein kinase reactions observed in the in vitro experiments remains problematic in the absence of precise knowledge on the "effective" or free concentrations of intracellular polyamines.

Animals↗
PubMed1996

Characterisation of a functional polyamine site on rat mast cells: association with a NMDA receptor macrocomplex.

Polyamines can modulate activation of N-methyl-D-aspartate (NMDA) receptors by binding to a specific polyamine site associated with a NMDA receptor macrocomplex. Polyamines induce histamine release from mast cells, although the mechanism had not been defined. We have examined whether spermine, a natural polyamine, and compound 48/80, regarded as a synthetic polyamine, activate mast cells by a polyamine site associated with a NMDA receptor macrocomplex. Spermine induced secretion of histamine from rat peritoneal mast cells and rat brain mast cells in a concentration-dependent manner. Rat peritoneal mast cells were used as a model system to explore the effects of NMDA antagonists on polyamine-induced histamine release. Ifenprodil, MK801 and arcaine inhibited histamine secretion from mast cells exposed to polyamines; the percentage inhibition was greater against spermine than compound 48/80. These data support the proposal that spermine (and possibly compound 48/80) induce histamine release from mast cells by interacting with a specific polyamine site on a NMDA receptor complex.

Animals↗
PubMed1992

Polyamine metabolism in enterocytes isolated from newborn pigs.

In the pig, the growth of intestinal mucosa is very intense after birth. Since the polyamines are key elements affecting cell proliferation and differentiation, the present work was undertaken in order to know whether this hypertrophy is associated with an adaptation of polyamine metabolism. Villus enterocytes isolated from pig immediately after birth or 2 days later were found to contain similar amounts of putrescine, spermidine and spermine, i.e., 0.23; 0.41 and 1.24 nmol/10(6) cells, respectively. At birth, despite a relatively high ODC activity, putrescine synthesis from 1 mM L-arginine or 2 mM L-glutamine was very low in isolated enterocytes (6.4 +/- 3.8 pmol/10(6) cells per 30 min), while spermidine and spermine production were not detectable. This could be explained by a very low L-ornithine generation from both amino acids and to an inhibitory effect of polyamines on ODC activity. Two days later, polyamine synthesis from L-arginine remained undetectable despite a higher L-ornithine generation. This was concomitant with a dramatic fall in ODC activity. At both stages, enterocytes were able to take up polyamines from the extracellular medium in a temperature-dependent manner. It is concluded that de-novo synthesis of polyamines from L-arginine or L-glutamine does not play a significant role in the control of polyamine content of pig enterocytes during the postnatal period. In contrast, polyamine uptake by enterocytes would contribute to maintain a steady-state polyamine content during this period.

Animals↗