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Feedback Inhibition (feedback + inhibition)
Selected AbstractsNonlinear Dynamics of Regulation of Bacterial trpOperon: Model Analysis of Integrated Effects of Repression, Feedback Inhibition, and AttenuationBIOTECHNOLOGY PROGRESS, Issue 4 2002Zhi-Long Xiu The trpoperon encodes the five genes for the enzymes required to convert chorismate to tryptophan, and its switching on and off is controlled by both feedback repression and attenuation in response to different levels of tryptophan in the cell. Repression of the operon occurs when tryptophan concentration is high, and attenuation fine-tunes the transcription level at a lower cellular concentration of tryptophan. An extended mathematical model is established in this study to describe the switching on and off of the trpoperon by considering the integrated effects of repression and attenuation. The influences of cell growth rate on the biosynthesis of tryptophan, stability and dynamic behavior of the trpoperon are investigated. Sustained oscillations of tryptophan levels are predicted from the regulated turning on and off of the trpoperon. It is interesting to note that during such oscillations the regulation of transcription displays a kind of "on" and "off" state in terms of gene expression, indicating the existence of a genetic circuit or switch in the regulation of the trpoperon. Time lags between transcription and translation are also predicted and may explain the occurrence of such oscillation phenomenon. [source] Feedback inhibition of action potential discharge by endogenous adenosine enhancement of the medium afterhyperpolarizationTHE JOURNAL OF PHYSIOLOGY, Issue 5 2009Ming Ruan Phasic activity in supraoptic nucleus vasopressin neurones is characterized by alternating periods of activity (bursts) and silence. During bursts, activation of a medium afterhyperpolarization induces spike frequency adaptation. Antagonism of A1 adenosine receptors within the supraoptic nucleus decreases spike frequency adaptation and prolongs phasic bursts in vivo, indicating that endogenous adenosine contributes to spike frequency adaptation. Here we used sharp electrode intracellular recordings from supraoptic nucleus neurones in hypothalamic explants to show that endogenous adenosine increases medium afterhyperpolarization amplitude to enhance spike frequency adaptation during phasic bursts. Superfusion of the A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT, 10 ,m) increased intraburst firing rate of phasic neurones (by 2.0 ± 0.7 spikes s,1, P= 0.03) and burst duration (by 141 ± 113 s, P= 0.03). The CPT-induced increase in intraburst firing rate developed over the first few seconds of firing and persisted thereafter. In a separate series of experiments, CPT reduced the amplitude of the medium afterhyperpolarization evoked by a 1 s 20 Hz spike train (by 0.8 ± 0.3 mV, P < 0.001) in supraoptic nucleus neurones; this inhibition was not prevented by 3 mm CsCl (0.8 ± 0.1 mV decrease, P < 0.01) to block the afterdepolarization (which overlaps temporally with the medium afterhyperpolarization). In the presence of apamin to block the medium afterhyperpolarization, CPT did not alter afterdepolarization amplitude. Taken together, these data show that endogenous adenosine enhances medium afterhyperpolarization amplitude to contribute to spike frequency adaptation in phasic supraoptic nucleus neurones. [source] Fat as a fuel: emerging understanding of the adipose tissue,skeletal muscle axisACTA PHYSIOLOGICA, Issue 4 2010K. N. Frayn Abstract The early pioneers in the field of metabolism during exercise such as Lindhard and Krogh understood the importance of fat as a fuel for muscle contraction. But they could not have understood the details of the pathways involved, as neither the metabolic role of adipose tissue nor the transport role of non-esterified fatty acids (NEFA) in the plasma was clearly understood at the time. We now recognize that the onset of muscular contraction coincides with an increase in the delivery of NEFA from adipose tissue, probably coordinated by the sympatho-adrenal system. During light exercise, adipose tissue-derived NEFA make up the majority of the oxidative fuel used by muscle. As exercise is prolonged, the importance of NEFA increases. The onset of exercise is marked by an increased proportion of NEFAs entering ,-oxidation rather than re-esterification and recycling. At moderate intensities of exercise, other sources of fat, potentially plasma- and intramyocellular-triacylglycerol, supplement the supply of plasma NEFA. The delivery of NEFA is augmented by increased adipose tissue blood flow and by other stimuli such as atrial natriuretic peptide. Only during high-intensity exercise is there a failure of adipose tissue to deliver sufficient fatty acids for muscle (which is coupled with an inability of muscle to use them, even when fatty acids are supplied artificially). This limitation of adipose tissue NEFA delivery may reflect some feedback inhibition of lipolysis, perhaps via lactate, or possibly ,-adrenergic inhibition of lipolysis at very high catecholamine concentrations. [source] AMP-activated protein kinase , a sensor of glycogen as well as AMP and ATP?ACTA PHYSIOLOGICA, Issue 1 2009A. McBride Abstract The classical role of the AMP-activated protein kinase (AMPK) is to act as a sensor of the immediate availability of cellular energy, by monitoring the concentrations of AMP and ATP. However, the , subunits of AMPK contain a glycogen-binding domain, and in this review we develop the hypothesis that this is a regulatory domain that allows AMPK to act as a sensor of the status of cellular reserves of energy in the form of glycogen. We argue that the pool of AMPK that is bound to the glycogen particle is in an active state when glycogen particles are fully synthesized, causing phosphorylation of glycogen synthase at site 2 and providing a feedback inhibition of further extension of the outer chains of glycogen. However, when glycogen becomes depleted, the glycogen-bound pool of AMPK becomes inhibited due to binding to ,1,6-linked branch points exposed by the action of phosphorylase and/or debranching enzyme. This allows dephosphorylation of site 2 on glycogen synthase by the glycogen-bound form of protein phosphatase-1, promoting rapid resynthesis of glycogen and replenishment of glycogen stores. This is an extension of the classical role of AMPK as a ,guardian of cellular energy', in which it ensures that cellular energy reserves are adequate for medium-term requirements. The literature concerning AMPK, glycogen structure and glycogen-binding proteins that led us to this concept is reviewed. [source] Intra- and inter-allelic ordering of T cell receptor , chain gene assemblyEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2005Bernard Khor Abstract Allelic exclusion at the TCR, locus mandates that gene assembly be regulated in a manner that permits feedback inhibition of further complete TCR, rearrangements upon pre-TCR expression. Here we show that assembly of TCR, chain genes from V,, D, and J, gene segments is intra-allelically ordered, proceeding primarily through DJ,, and not VD,, intermediates. This ensures that V, to DJ, rearrangement, which can be feedback inhibited, is the final step in the assembly process. A newly assembled VDJ, rearrangement must be tested to determine if it is in-frame before V, to DJ, rearrangement is permitted on the alternate allele. This inter-allelic ordering may occur through a general inefficiency of V, to DJ, rearrangement and/or through static differences in accessibility of the two TCR, alleles. However, we find that within the regulatory context of allelic exclusion, V, to DJ, rearrangement proceeds to completion on both alleles. Furthermore, all possible VDJ, rearrangements are not completed on one allele before V, to DJ, rearrangement is initiated on the alternate allele. Together, these data support a dynamic model of inter-allelic accessibility that permits the ordered and efficient assembly of complete variable region genes on both TCR, alleles during T cell development. [source] Odour-evoked [Ca2+] transients in mitral cell dendrites of frog olfactory glomeruliEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2001Kerry Delaney Abstract We measured Ca2+ concentration, [Ca2+], transients in mitral cell distal apical dendritic tufts produced by physiological odour stimulation of the olfactory epithelium and electrical stimulation of the olfactory nerve (ON) using two-photon scanning and conventional wide-field microscopy of Ca2+ -Green-1 dextran in an in vitro frog nose,brain preparation. Weak or strong ON shock-evoked fluorescence transients always had short latency with an onset 0,10 ms after the onset of the bulb local field potential, rapidly increasing to a peak of up to 25% fractional fluorescence change (,F/F) in 10,30 ms, were blocked by 10 µm CNQX, decaying with a time constant of about 1 s. With stronger ON shocks that activated many receptor axons, an additional, delayed, sustained AP5-sensitive component (peak at ,,0.5 s, up to 40% ,F/F maximum) could usually be produced. Odour-evoked [Ca2+] transients sometimes displayed a rapid onset phase that peaked within 50 ms but always had a sustained phase that peaked 0.5,1.5 s after onset, regardless of the strength of the odour or the amplitude of the response. These were considerably larger (up to 150% ,F/F) than those evoked by ON shock. Odour-evoked [Ca2+] transients were also distinguished from ON shock-evoked transients by tufts in different glomeruli responding with different delays (time to onset differed by up to 1.5 s between different tufts for the same odour). Odour-evoked [Ca2+] transients were increased by AMPA-kainate receptor blockade, but substantially blocked by AP5. Electrical stimulation of the lateral olfactory tract (5,6 stimuli at 10 Hz) that evoked granule cell feedback inhibition, blocked 60,100% of the odour-evoked [Ca2+] transient in tufts when delivered within about 0.5 s of the odour. LOT-mediated inhibition was blocked by 10 µm bicuculline. [source] The isochronic band hypothesis and climbing fibre regulation of motricity: an experimental studyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2001Masaji Fukuda Abstract The dynamic organization of the olivocerebellar afferent input to Purkinje cells was examined in rat cerebellar cortex. The distribution of synchronous Purkinje cell complex spike activity was characterized, bilaterally, utilizing multiple electrode recordings in crus IIa folium under ketamine anaesthesia. The results confirmed the existence of rostrocaudal complex spike isochronicity bands with a mediolateral width of 500 µm. For a given band, no finer spatial submicrostructures could be discerned at a first-order approximation (two-dimensional projection). Closer analysis determined that isochronicity between bands is not continuous in space but demonstrates discrete discontinuities at the mediolateral boundaries. Principal component multivariate analysis revealed that the first principal component of the spatio-temporal variance is synchronicity along the rostrocaudal band with a decreased level of coupling in the mediolateral direction at the band boundary. Furthermore, this discrete banding isochronicity is organized by the distribution of feedback inhibition from the cerebellar nuclei on to the inferior olive nucleus. The usual multiple band structure can be dynamically altered to a single wide-band dynamic architecture, or to other patterns of activity, as may be required by movement coordination. [source] The N -acetylglutamate synthase/N -acetylglutamate kinase metabolon of Saccharomyces cerevisiae allows co-ordinated feedback regulation of the first two steps in arginine biosynthesisFEBS JOURNAL, Issue 5 2003Katia Pauwels In Saccharomyces cerevisiae, which uses the nonlinear pathway of arginine biosynthesis, the first two enzymes, N -acetylglutamate synthase (NAGS) and N -acetylglutamate kinase (NAGK), are controlled by feedback inhibition. We have previously shown that NAGS and NAGK associate in a complex, essential to synthase activity and protein level [Abadjieva, A., Pauwels, K., Hilven, P. & Crabeel, M. (2001) J. Biol. Chem.276, 42869,42880]. The NAGKs of ascomycetes possess, in addition to the catalytic domain that is shared by all other NAGKs and whose structure has been determined, a C-terminal domain of unknown function and structure. Exploring the role of these two domains in the synthase/kinase interaction, we demonstrate that the ascomycete-specific domain is required to maintain synthase activity and protein level. Previous results had suggested a participation of the third enzyme of the pathway, N -acetylglutamylphosphate reductase, in the metabolon. Here, genetic analyses conducted in yeast at physiological level, or in a heterologous background, clearly demonstrate that the reductase is dispensable for synthase activity and protein level. Most importantly, we show that the arginine feedback regulation of the NAGS and NAGK enzymes is mutually interdependent. First, the kinase becomes less sensitive to arginine feedback inhibition in the absence of the synthase. Second, and as in Neurospora crassa, in a yeast kinase mutant resistant to arginine feedback inhibition, the synthase becomes feedback resistant concomitantly. We conclude that the NAGS/NAGK metabolon promotes the co-ordination of the catalytic activities and feedback regulation of the first two, flux controlling, enzymes of the arginine pathway. [source] Regulation of immunoglobulin heavy-chain gene rearrangementsIMMUNOLOGICAL REVIEWS, Issue 1 2004Dipanjan Chowdhury Summary:, Regulated assembly of antigen receptor gene segments to produce functional genes is a hallmark of B- and T-lymphocyte development. The immunoglobulin heavy-chain (IgH) and T-cell receptor ,-chain genes rearrange first in B and T lineages, respectively. Both loci require two recombination events to assemble functional genes; D-to-J recombination occurs first followed by V-to-DJ recombination. Despite similarities in overall rearrangement patterns, each locus has unique regulatory features. Here, we review the characteristics of IgH gene rearrangements such as developmental timing, deletion versus inversion, DH gene segment utilization, ordered recombination of VH gene segments, and feedback inhibition of rearrangement in pre-B cells. We summarize chromatin structural features of the locus before and during recombination and, wherever possible, incorporate these into working hypotheses for understanding regulation of IgH gene recombination. The picture emerges that the IgH locus is activated in discrete, independently regulated domains. A domain encompassing DH and JH gene segments is activated first, within which recombination is initiated. VH genes are activated subsequently and, in part, by interleukin-7. These observations lead to a model for feedback inhibition of IgH rearrangements. [source] Statins enhance toll-like receptor 4-mediated cytokine gene expression in astrocytes: Implication of Rho proteins in negative feedback regulationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2008Gregory W. Konat Abstract Toll-like receptors (TLRs) are sentinels of innate immunity that recognize pathogenic molecules and trigger inflammatory response. Because inflammatory mediators are detrimental to the host, the TLR response is regulated by feedback inhibition. Statins, the inhibitors of isoprenoid biosynthesis, have been shown to be potent modulators of TLR activity, and this modulation may provide insight regarding mechanisms of the feedback inhibition. In the present study, we examined feedback mechanisms that regulate TLR4 activity in astrocytes using statins to perturb postligational signaling. Astrocytic cultures established from newborn rat brains were exposed to lipopolysaccharide (LPS), the ligand for TLR4. The up-regulation of expression of genes encoding interleukin (IL)-1,, IL-6, and tumor necrosis factor-, (TNF,) was determined by real-time RT-PCR. Pretreatment of the cells with either atorvastatin or simvastatin enhanced the LPS-induced up-regulation of cytokine gene expression. The most profound enhancement of approximately 17-fold was observed for the Il-6 gene. The enhancements for the Tnfa and Il-1b genes were approximately 5- and 3.5-fold, respectively. Mevalonate fully reversed the effects of statins, indicating that these drugs act through the inhibition of isoprenoid synthesis. The inhibition of protein geranylgeranylation, but not protein farnesylation, mimicked the effects of statins, strongly indicating that the enhancement is mediated by the Rho proteins. In support of this notion, pretreatment of cells with toxin B, a specific inhibitor of the Rho proteins, also enhanced LPS-triggered up-regulation of the cytokine genes. These results indicate that the Rho proteins are involved in the activation of negative feedback inhibition of TLR4 signaling in astrocytes. © 2007 Wiley-Liss, Inc. [source] KINETICS OF NITRATE, AMMONIUM, AND UREA UPTAKE BY FOUR INTERTIDAL SEAWEEDS FROM NEW ZEALAND,JOURNAL OF PHYCOLOGY, Issue 3 2004Julia C. Phillips The competitive ability for N uptake by four intertidal seaweeds, Stictosiphonia arbuscula (Harvey) King et Puttock, Apophlaea lyallii Hook. f. et Harvey, Scytothamnus australis Hook. f. et Harvey, and Xiphophora gladiata (Labillardičre) Montagne ex Harvey, from New Zealand is described by the uptake kinetics for NO3,, NH4+, and urea. This is the first study to report uptake kinetics for N uptake by a range of southern hemisphere intertidal seaweeds in relation to season and zonation. Species growing at the highest shore positions had higher NO3, and urea uptake at both high and low concentrations and had unsaturable NH4+ uptake in both summer and winter. Although there was evidence of some feedback inhibition of Vmax for NO3, uptake by Stictosiphonia arbuscula growing at the lower vertical limits of its range, rates were high compared with species growing lower on the shore. Our results highlight the superior competitive ability for N uptake of certain high intertidal seaweeds, and consistent with our previous findings we can conclude that intertidal seaweeds in southeast New Zealand are adapted to maximizing N acquisition in a potentially N-limiting environment. [source] The rediscovery and isolation of TFPIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2003G. J. Broze Jr Summary., Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that produces factor (F)Xa-dependent feedback inhibition of the factor VIIa/tissue factor (FVIIa/TF) catalytic complex that is responsible for the initiation of coagulation. Since 1985, when Rapaport and colleagues reported that the lipoprotein fraction of plasma contained a FXa-dependent inhibitor of FVIIa/TF, myriad articles have established its biochemical structure, its mechanism of action, and its physiological importance. This brief personal account reviews historical studies that established the existence of the inhibitor and the events that led to its initial isolation. [source] Enhanced glutathione production by using low-pH stress coupled with cysteine addition in the treatment of high cell density culture of Candida utilisLETTERS IN APPLIED MICROBIOLOGY, Issue 5 2008G. Liang Abstract Aims:, To investigate the effects of pH stress coupled with cysteine addition on glutathione (GSH) production in the treatment of high cell density culture of Candida utilis. Methods and Results:, We have previously observed that most Candida utilis cells remained viable after being subjected to pH at 1·2 for 3 h and that some intracellular GSH leaked into the medium. A cysteine addition strategy was applied in fed-batch production of GSH. A single cysteine addition resulted in higher GSH yield than two separate additions without pH stress. An increase in intracellular GSH content triggered inhibition of ,-glutamylcysteine synthetase (,-GCS). A strategy that combines cysteine addition with low-pH stress was developed to relieve the inhibition of ,-GCS. Conclusion:, Without pH stress, single shot and double shot cysteine addition yielded a total GSH of 1423 and 1325 mg l,1. In comparison, a low-pH stress counterpart resulted in a total GSH of 1542 and 1730 mg l,1, respectively. With low-pH stress, we observed GSH secretion into the medium at 673 and 558 mg l,1 and an increase in the ,-GCS activity by 1·2- and 1·5-fold, respectively. The specific GSH production yield increased from 1·76% to 1·91% (w/w) for single shot, and 1·64% to 2·14% for double shots. Significance and Impact of the Study:, Low-pH shift was applied to alleviate the feedback inhibition of intracellular GSH on ,-GCS activity by secreting GSH into the medium. This strategy is coupled with cysteine addition to enhance GSH production in Candida utilis. [source] Physiological girdling of pine trees via phloem chilling: proof of conceptPLANT CELL & ENVIRONMENT, Issue 1 2007KURT JOHNSEN ABSTRACT Quantifying below-ground carbon (C) allocation is particularly difficult as methods usually disturb the root,mycorrhizal,soil continuum. We reduced C allocation below ground of loblolly pine trees by: (1) physically girdling trees and (2) physiologically girdling pine trees by chilling the phloem. Chilling reduced cambium temperatures by approximately 18 °C. Both methods rapidly reduced soil CO2 efflux, and after approximately 10 days decreased net photosynthesis (Pn), the latter indicating feedback inhibition. Chilling decreased soil-soluble C, indicating that decreased soil CO2 efflux may have been mediated by a decrease in root C exudation that was rapidly respired by microbes. These effects were only observed in late summer/early autumn when above-ground growth was minimal, and not in the spring when above-ground growth was rapid. All of the effects were rapidly reversed when chilling was ceased. In fertilized plots, both chilling and physical girdling methods reduced soil CO2 efflux by approximately 8%. Physical girdling reduced soil CO2 efflux by 26% in non-fertilized plots. This work demonstrates that phloem chilling provides a non-destructive alternative to reducing the movement of recent photosynthate below the point of chilling to estimate C allocation below ground on large trees. [source] Responses of CAM species to increasing atmospheric CO2 concentrationsPLANT CELL & ENVIRONMENT, Issue 8 2000P. M. Drennan ABSTRACT Crassulacean acid metabolism (CAM) species show an average increase in biomass productivity of 35% in response to a doubled atmospheric CO2 concentration. Daily net CO2 uptake is similarly enhanced, reflecting in part an increase in chlorenchyma thickness and accompanied by an even greater increase in water-use efficiency. The responses of net CO2 uptake in CAM species to increasing atmospheric CO2 concentrations are similar to those for C3 species and much greater than those for C4 species. Increases in net daily CO2 uptake by CAM plants under elevated atmospheric CO2 concentrations reflect increases in both Rubisco-mediated daytime CO2 uptake and phosphoenolpyruvate carboxylase (PEPCase)-mediated night-time CO2 uptake, the latter resulting in increased nocturnal malate accumulation. Chlorophyll contents and the activities of Rubisco and PEPCase decrease under elevated atmospheric CO2, but the activated percentage for Rubisco increases and the KM(HCO3,) for PEPCase decreases, resulting in more efficient photosynthesis. Increases in root:shoot ratios and the formation of additional photosynthetic organs, together with increases in sucrose-Pi synthase and starch synthase activity in these organs under elevated atmospheric CO2 concentrations, decrease the potential feedback inhibition of photosynthesis. Longer-term studies for several CAM species show no downward acclimatization of photosynthesis in response to elevated atmospheric CO2 concentrations. With increasing temperature and drought duration, the percentage enhancement of daily net CO2 uptake caused by elevated atmospheric CO2 concentrations increases. Thus net CO2 uptake, productivity, and the potential area for cultivation of CAM species will be enhanced by the increasing atmospheric CO2 concentrations and the increasing temperatures associated with global climate change. [source] Ligand binding to the inhibitory and stimulatory GTP cyclohydrolase I/GTP cyclohydrolase I feedback regulatory protein complexesPROTEIN SCIENCE, Issue 4 2001Toshie Yoneyama BH4, 6R - l - erythro -5,6,7,8-tetrahydrobiopterin; GFRP, GTP cyclohydrolase I feedback regulatory protein Abstract GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates feedback inhibition of GTP cyclohydrolase I activity by 6R - l - erythro -5,6,7,8-tetrahydrobiopterin (BH4), which is an essential cofactor for key enzymes producing catecholamines, serotonin, and nitric oxide as well as phenylalanine hydroxylase. GFRP also mediates feed-forward stimulation of GTP cyclohydrolase I activity by phenylalanine at subsaturating GTP levels. These ligands, BH4 and phenylalanine, induce complex formation between one molecule of GTP cyclohydrolase I and two molecules of GFRP. Here, we report the analysis of ligand binding using the gel filtration method of Hummel and Dreyer. BH4 binds to the GTP cyclohydrolase I/GFRP complex with a Kd of 4 ,M, and phenylalanine binds to the protein complex with a Kd of 94 ,M. The binding of BH4 is enhanced by dGTP. The binding stoichiometrics of BH4 and phenylalanine were estimated to be 10 molecules of each per protein complex, in other words, one molecule per subunit of protein, because GTP cyclohydrolase I is a decamer and GFRP is a pentamer. These findings were corroborated by data from equilibrium dialysis experiments. Regarding ligand binding to free proteins, BH4 binds weakly to GTP cyclohydrolase I but not to GFRP, and phenylalanine binds weakly to GFRP but not to GTP cyclohydrolase I. These results suggest that the overall structure of the protein complex contributes to binding of BH4 and phenylalanine but also that each binding site of BH4 and phenylalanine may be primarily composed of residues of GTP cyclohydrolase I and GFRP, respectively. [source] Roles of distinct glutamate receptors in induction of anti-Hebbian long-term potentiationTHE JOURNAL OF PHYSIOLOGY, Issue 6 2008Dimitri M. Kullmann Many glutamatergic synapses on interneurons involved in feedback inhibition in the CA1 region of the hippocampus exhibit an unusual form of long-term potentiation (LTP) that is induced only if presynaptic glutamate release occurs when the postsynaptic membrane potential is relatively hyperpolarized. We have named this phenomenon ,anti-Hebbian' LTP because it is prevented by postsynaptic depolarization during afferent activity, and hence its induction requirements are opposite to those of Hebbian NMDA receptor-dependent LTP. This symposium report addresses the roles of distinct glutamate receptors in the induction of anti-Hebbian LTP. Inwardly rectifying Ca2+ -permeable AMPA receptors mediate fast glutamatergic signalling at synapses that exhibit this form of LTP, and they are highly likely to mediate the instructive signal that triggers the cascade leading to synapse strengthening. NMDA receptors, on the other hand, play no role, nor do they contribute substantially to synaptic transmission at synapses that exhibit anti-Hebbian LTP. Both kainate and group I metabotropic glutamate receptors are abundant in at least some interneurons in the feedback inhibitory circuit. Delineating the roles of kainate receptors has been hampered by sub-optimal pharmacological tools. As for group I metabotropic glutamate receptors, their role in anti-Hebbian LTP is permissive at the very least in some interneuron types, although an instructive role has been suggested in other forms of activity-dependent plasticity. [source] Auto-inhibition of rat parallel fibre,Purkinje cell synapses by activity-dependent adenosine releaseTHE JOURNAL OF PHYSIOLOGY, Issue 2 2007Mark J. Wall Adenosine is an important signalling molecule involved in a large number of physiological functions. In the brain these processes are as diverse as sleep, memory, locomotion and neuroprotection during episodes of ischaemia and hypoxia. Although the actions of adenosine, through cell surface G-protein-coupled receptors, are well characterized, in many cases the sources of adenosine and mechanisms of release have not been defined. Here we demonstrate the activity-dependent release of adenosine in the cerebellum using a combination of electrophysiology and biosensors. Short trains of electrical stimuli delivered to the molecular layer in vitro, release adenosine via a process that is both TTX and Ca2+ sensitive. As ATP release cannot be detected, adenosine must either be released directly or rapidly produced by highly localized and efficient extracellular ATP breakdown. Since adenosine release can be modulated by receptors that act on parallel fibre,Purkinje cell synapses, we suggest that the parallel fibres release adenosine. This activity-dependent adenosine release exerts feedback inhibition of parallel fibre,Purkinje cell transmission. Spike-mediated adenosine release from parallel fibres will thus powerfully regulate cerebellar circuit output. [source] Concurrent interactions of heme and FLU with Glu tRNA reductase (HEMA1), the target of metabolic feedback inhibition of tetrapyrrole biosynthesis, in dark- and light-grown Arabidopsis plantsTHE PLANT JOURNAL, Issue 6 2004David Goslings Summary The regulation of tetrapyrrole biosynthesis in higher plants has been attributed to metabolic feedback inhibition of Glu tRNA reductase by heme. Recently, another negative regulator of tetrapyrrole biosynthesis has been discovered, the FLU protein. During an extensive second site screen of mutagenized flu seedlings a suppressor of flu, ulf3, was identified that is allelic to hy1 and encodes a heme oxygenase. Increased levels of heme in the hy1 mutant have been implicated with inhibiting Glu tRNA reductase and suppressing the synthesis of , -aminolevulinic acid (ALA) and Pchlide accumulation. When combined with hy1 or ulf3 upregulation of ALA synthesis and overaccumulation of protochlorophyllide in the flu mutants were severely suppressed supporting the notion that heme antagonizes the effect of the flu mutation by inhibiting Glu tRNA reductase independently of FLU. The coiled-coil domain at the C-terminal end of Glu tRNA reductase interacts with FLU, whereas the N-terminal site of Glu tRNA reductase that is necessary for the inhibition of the enzyme by heme is not required for this interaction. The interaction with FLU is specific for the Glu tRNA reductase encoded by HEMA1 that is expressed in photosynthetically active tissues. FLU seems to be part of a second regulatory circuit that controls chlorophyll biosynthesis by interacting directly with Glu tRNA reductase not only in etiolated seedlings but also in light-adapted green plants. [source] Modulation of growth hormone action by sex steroidsCLINICAL ENDOCRINOLOGY, Issue 4 2006Udo J. Meinhardt Summary Growth hormone (GH) is a major regulator of growth, somatic development and body composition. Sex steroids can act centrally by regulating GH secretion and peripherally modulating GH responsiveness. This review addresses data of potential clinical relevance on how sex steroids modulate GH secretion and action, aiming to increase the understanding of sex steroid/GH interactions and leading to improved management of patients. Sex steroids regulate GH secretion directly as well as indirectly through IGF-I modulation. Testosterone stimulates GH secretion centrally, an effect dependent on prior aromatization to oestrogen. Oestrogen stimulates GH secretion indirectly by reducing IGF-I feedback inhibition. Whether oestrogen stimulates GH secretion centrally in females is unresolved. Gonadal steroids modify the metabolic effects of GH. Testosterone amplifies GH stimulation of IGF-I, sodium retention, substrate metabolism and protein anabolism while exhibiting similar but independent actions of its own. Oestrogen attenuates GH action by inhibiting GH-regulated endocrine function of the liver. This is a concentration-dependent phenomenon that arises invariably from oral administration of therapeutic doses of oestrogen, an effect that can be avoided by using a parenteral route. This strong modulatory effect of gonadal steroids on GH responsiveness provides insights into the biological basis of sexual dimorphism in growth, development and body composition and practical information for the clinical endocrinologist. It calls for an appraisal of the diagnostic criteria for GH deficiency of GH stimulation tests, which currently are based on arbitrary cut-offs that do not take into account the shifting baseline from the changing gonadal steroid milieu. In the management of GH deficiency in the hypopituitary female, oestrogen should be administered by a nonoral route. In hypopituitary men, androgens should be replaced concurrently to maximize the benefits of GH. In the general population, the metabolic consequences of long-term treatment of women with oral oestrogen compounds, including selective oestrogen receptor modulators, are largely unknown and warrant study. [source] | |||||||||||||||||||||||||