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At least 127 records · Page 7Linked to original sources
PubMed2002

Dynamic regulation of GABA(A) receptors at synaptic sites.

gamma-Aminobutyric acid type A receptors (GABA(A)Rs) mediate fast synaptic inhibition in brain and spinal cord. They are ligand-gated ion channels composed of numerous distinct subunit combinations. For efficient synaptic transmission, GABA(A)Rs need to be localized to and anchored at postsynaptic sites in precise apposition to presynaptic nerve terminals that release the neurotransmitter GABA. Neurons therefore require distinct mechanisms to regulate intracellular vesicular protein traffic, plasma membrane insertion, synaptic clustering and turnover of GABA(A)Rs. The GABA(A) receptor-associated protein GABARAP interacts with the gamma2 subunit of GABA(A)Rs and displays high homology to proteins involved in membrane fusion underlying Golgi transport and autophagic processes. The binding of GABARAP with NSF, microtubules and gephyrin together with its localization at intracellular membranes suggests a role in GABA(A)R targeting and/or degradation. Growth factor tyrosine kinase receptor activation is involved in the control of GABA(A)R levels at the plasma membrane. In particular insulin recruits GABA(A)Rs to the cell surface. Furthermore, the regulation of GABA(A)R surface half-life can also be the consequence of negative modulation at the proteasome level. Plic-1, a ubiquitin-like protein binds to both the proteasome and GABA(A)Rs and the Plic1-GABA(A)R interaction is important for the maintenance of GABA-activated current amplitudes. At synaptic sites, GABA(A)Rs are clustered via gephyrin-dependent and gephyrin-independent mechanisms and may subsequently become internalized via clathrin-mediated endocytosis underlying receptor recycling or degradation processes. This article discusses these recent data in the field of GABA(A)R dynamics.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Dynamic regulation of intracellular Ca2+ concentration in aortic endothelial cells.

In non-excitable cells, a Ca2+ entry pathway is opened after the depletion of intracellular Ca2+ store sites. We have tried to estimate the sensitivity of this pathway to Ca2+ release using bovine aortic endothelial cells. Single application of a high concentration (30 microM) of ATP released almost all stored Ca2+ in Ca(2+)-free extracellular solution, whereas a low concentration of ATP (30 nM) produced a partial (57.3 +/- 3.0%) release of Ca2+. By 10 min of Ca2+ re-perfusion, the Ca2+ store site was reloaded to 97.1% of its initial filling state. When thapsigargin was applied to this cell in Mn2+ solution, Mn(2+)-induced quenching of fura-2 dye started when 19.3 +/- 5.3% of Ca2+ release, produced by 30 nM ATP, had occurred. Therefore, Ca2+ release required for Mn2+ entry was estimated as 11.1 +/- 3.0% of stored Ca2+. These results indicate that intracellular Ca2+ concentration is controlled dynamically by simultaneously occurring Ca2+ release and entry in bovine aortic endothelial cells.

Adenosine Triphosphatases↗
PubMed2002

Dynamic regulation of T cell immunity by CD43.

During a viral response, Ag-specific effector T cells show dramatically increased binding by the mAb 1B11 and the lectin peanut agglutinin (PNA). We investigated the contribution of CD43 expression to 1B11 and PNA binding as well as its role in generation and maintenance of a CD8 T cell response. Analysis of CD43(-/-) mice revealed no increased 1B11 binding and reduced PNA binding on virus-specific CD8 T cells from -/- mice compared with +/+ mice. Furthermore, we examined the role of CD43 in the kinetics of an immune response. We show that CD43 expression modestly effects generation of a primary virus-specific CD8 T cell response in vivo but plays a more significant role in trafficking of CD8 T cells to tissues such as the brain. More interestingly, CD43 plays a role in the contraction of the immune response, with CD43(-/-) mice showing increased numbers of Ag-specific CD8 T cells following initial expansion. Following the peak of expansion, Ag-specific CD8 T cells from -/- mice show similar proliferation but demonstrate increased Bcl-2 levels and decreased apoptosis of Ag-specific effector CD8 T cells in vitro. Consistent with a delay in the down-modulation of the immune response, following chronic viral infection CD43(-/-) mice show increased morbidity. These data suggest a dynamic role of CD43 during an immune response: a positive regulatory role in costimulation and trafficking of T cells to the CNS and a negative regulatory role in the down-modulation of an immune response.

Animals↗
PubMed2003

Dynamic regulation of Src-family kinases by CD45 in B cells.

CD45 is a key protein tyrosine phosphatase regulating Src-family protein tyrosine kinases (Src-PTKs) in lymphocytes; precisely how it exerts its effect remains controversial, however. We previously demonstrated that CD45 negatively regulates Lyn in the WEHI-231 B-cell line. Here we show that negative regulation by CD45 is physiologically significant in B cells and that some CD45 is constitutively associated with glycolipid-enriched microdomains (GEMs), where it inhibits Src-PTKs by dephosphorylating both the negative and the positive regulatory sites. Upon B-cell receptor (BCR) ligation, however, CD45 dissociates from GEMs within 30 seconds, inducing phosphorylation of 2 regulatory sites and activation of Src-PTKs, but subsequently reassociates with the GEMs within 15 minutes. Disruption of GEMs with methyl-beta-cyclodextrin results in abrogation of BCR-induced apoptosis in WEHI-231 cells, suggesting GEMs are critical to signals leading to the fate determination. We propose that the primary function of CD45 is inhibition of Src-PTKs and that the level of Src-PTK activation and the B-cell fate are determined in part by dynamic behavior of CD45 with respect to GEMs.

Animals↗
PubMedDate not supplied

Activity-driven computational strategies of a dynamically regulated integrate-and-fire model neuron.

Activity-dependent slow biochemical regulation processes, affecting intrinsic properties of a neuron, might play an important role in determining information processing strategies in the nervous system. We introduce second-order biochemical phenomena into a linear leaky integrate-and-fire model neuron together with a detailed kinetic description for synaptic signal transduction. In this framework, we investigate the membrane intrinsic electrical properties differentiation, showing the appearance of activity-dependent shifts between integration and temporal coincidence detection operating mode, for the single unit of a network.

Action Potentials↗
PubMed2003

Dynamic regulation of sensorimotor integration in human postural control.

Upright stance in humans is inherently unstable, requiring corrective action based on spatial-orientation information from sensory systems. One might logically predict that environments providing access to accurate orientation information from multiple sensory systems would facilitate postural stability. However, we show that, after a period in which access to accurate sensory information was reduced, the restoration of accurate information disrupted postural stability. In eyes-closed trials, proprioceptive information was altered by rotating the support surface in proportion to body sway (support surface "sway-referencing"). When the support surface returned to a level orientation, most subjects developed a transient 1-Hz body sway oscillation that differed significantly from the low-amplitude body sway typically observed during quiet stance. Additional experiments showed further enhancement of the 1-Hz oscillation when the surface transitioned from a sway-referenced to a reverse sway-referenced motion. Oscillatory behavior declined with repetition of trials, suggesting a learning effect. A simple negative feedback-control model of the postural control system predicted the occurrence of this 1-Hz oscillation in conditions where too much corrective torque is generated in proportion to body sway. Model simulations were used to distinguish between two alternative explanations for the excessive corrective torque generation. Simulation results favor an explanation based on the dynamic reweighting of sensory contributions to postural control rather than a load-compensation mechanism that scales torque in proportion to a fixed combination of sensory-orientation information.

Adaptation, Physiological↗
PubMed2006

Dynamic regulation of glycinergic input to spinal dorsal horn neurones by muscarinic receptor subtypes in rats.

Activation of spinal muscarinic acetylcholine receptors (mAChRs) inhibits nociception. However, the cellular mechanisms of this action are not fully known. In this study, we determined the role of mAChR subtypes in regulation of synaptic glycine release in the spinal cord. Whole-cell voltage-clamp recordings were performed on lamina II neurones in the rat spinal cord slices. The mAChR agonist oxotremorine-M significantly increased the frequency of glycinergic sIPSCs but not mIPSCs. Surprisingly, the effect of oxotremorine-M on sIPSCs was largely attenuated at a higher concentration. On the other hand, 1-10 microm oxotremorine-M dose-dependently increased the frequency of sIPSCs in rats pretreated with intrathecal pertussis toxin. Furthermore, oxotremorine-M also dose-dependently increased the frequency of sIPSCs in the presence of himbacine (an M2/M4 mAChR antagonist) or AF-DX116 (an M2 mAChR antagonist). The M3 mAChR antagonist 4-DAMP abolished the stimulatory effect of oxotremorine-M on sIPSCs. Interestingly, the GABA(B) receptor antagonist CGP55845 potentiated the stimulatory effect of oxotremorine-M on sIPSCs. In the presence of CGP55845, both himbacine and AF-DX116 similarly reduced the potentiating effect of oxotremorine-M on sIPSCs. Collectively, these data suggest that the M3 subtype is present on the somatodendritic site of glycinergic neurones and is mainly responsible for muscarinic potentiation of glycinergic input to spinal dorsal horn neurones. Concurrent stimulation of mAChRs on adjacent GABAergic interneurones attenuates synaptic glycine release through presynaptic GABA(B) receptors on glycinergic interneurones. This study illustrates a complex dynamic interaction between GABAergic and glycinergic synapses in the spinal cord dorsal horn.

Animals↗
PubMed1999

Activity-dependent refinement in the goldfish retinotectal system is mediated by the dynamic regulation of processes withdrawal: an in vivo imaging study.

Imaging of regenerating optic fibers in living adult goldfish was used to visualize arbor restructuring during activity-dependent refinement. A small number of neighboring retinal ganglion cells were labeled with DiI and observed in the tectum of the living animal for 5-7 hours during the period of activity-dependent refinement. In contrast to earlier stages of regeneration, many optic arbors were surprisingly stable, showing little or no change. The observed changes were mainly retractions, and these were affected by retinotopic position and activity. Axon branches in retinotopic positions changed by much smaller amounts than ectopic axons, but in fish with retinal tetrodotoxin impulse blockade, no systematic difference was observed as a function of tectal position. Otherwise, impulse blockade had no notable effects.

Animals↗
PubMed2004

Dynamic regulation of DNA methylation coupled transcriptional repression: BDNF regulation by MeCP2.

A recurrent theme in eukaryotic genome regulation stipulates that the properties of DNA are strongly influenced by the nucleoprotein complex into which it is assembled. Methylation of cytosine residues in vertebrate genomes has been implicated in influencing the assembly of locally repressive chromatin architecture. Current models suggest that covalent modification of DNA results in heritable, long-term transcriptional silencing. In October of 2003, two manuscripts were published that challenge important aspects of this model, suggesting that modulation of both DNA methylation itself, as well as the machinery implicated in its interpretation, are involved in acute gene regulation.

Animals↗
PubMed2006

Dynamic regulation and involvement of the heat shock transcriptional response in arsenic carcinogenesis.

The objective of this study is to better define induction of the heat shock response by arsenite, and to evaluation if induction of heat shock proteins (HSPs) contributes to the carcinogenic activity of arsenite. We show here that arsenite is a ubiquitous inducer of the heat shock response in mammalian cells: that it activated heat shock transcription factor 1 (HSF1) DNA-binding activity, enhanced hsp 70 promoter, and induced hsp70mRNA and synthesis of HSP chaperones. Using a high throughput hsp70 promoter-luciferase reporter assay, we observed a hormetic dose response where low concentrations of arsenite stimulated and high concentrations inhibited. Further, the response was time-dependent such that with longer times of incubation, the dose response shifted to the left. The effect of arsenite in inducing the hsp 70-luciferase reporter absolutely required a functional HSF1 as it was not observed in HSF1 minus cells but re-instated by expression of HSF1. Consistent with the suggestion that arsenic targets vicinal cysteine-SH, we showed that dithiothreitol blocked the effect of arsenite. Assays of cell viability and caspase showed that arsenite caused a dose-dependent increase in cell death by activation of caspase 3/7 and pre-induction of HSPs blunted these effects. Using anchorage independent cell growth as a late stage tumor promotion assay, we showed that low concentrations of arsenite had a growth promoting effect, which was enhanced by moderate heat shock. Our study provides evidence that induction of the heat shock response is a sensitive biomarker of arsenic exposure and that induction of HSPs likely contributes to the tumor promotion effect of arsenic.

Animals↗
PubMed1998

Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system.

The monoamines, serotonin, dopamine, norepinephrine, epinephrine and histamine, play a critical role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information in sensory, limbic, and motor systems. The primary mechanism for termination of monoaminergic neurotransmission is through reuptake of released neurotransmitter by Na+, CI-dependent plasma membrane transporters. A second family of transporters packages monoamines into synaptic and secretory vesicles by exchange of protons. Identification of those cells which express these two families of neurotransmitter transporters is an initial step in understanding what adaptive strategies cells expressing monoamine transporters use to establish the appropriate level of transport activity and thus attain the appropriate efficiency of monoamine storage and clearance. The most recent advances in this field have yielded several surprises about their function, cellular and subcellular localization, and regulation, suggesting that these molecules are not static and most likely are the most important determinants of extracellular levels of monoamines. Here, information on the localization of mRNAs for these transporters in rodent and human brain is summarized along with immunohistochemical information at the light and electron microscopic levels. Regulation of transporters at the mRNA level by manipulation in rodents and differences in transporter site densities by tomographic techniques as an index of regulation in human disease and addictive states are also reviewed. These studies have highlighted the presence of monoamine neurotransmitter transporters in neurons but not in glia in situ. The norepinephrine transporter is present in all cells which are both tyrosine hydroxylase (TH)- and dopamine beta-hydroxylase-positive but not in those cells which are TH- and phenyl-N-methyltransferase-positive, suggesting that epinephrine cells may have their own, unique transporter. In most dopaminergic cells, dopamine transporter mRNA completely overlaps with TH mRNA-positive neurons. However, there are areas in which there is a lack of one to one correspondence. The serotonin transporter (5-HTT) mRNA is found in all raphe nuclei and in the hypothalamic dorsomedial nucleus where the 5-HTT mRNA is dramatically reduced following immobilization stress. The vesicular monoamine transporter 2 (VMAT2) is present in all monoaminergic neurons including epinephrine- and histamine-synthesizing cells. Immunohistochemistry demonstrates that the plasma membrane transporters are present along axons, soma, and dendrites. Subcellular localization of DAT by electron microscopy suggests that these transporters are not at the synaptic density but are confined to perisynaptic areas, implying that dopamine diffuses away from the synapse and that contribution of diffusion to dopamine signalling may vary between brain regions. Interestingly, the presence of VMAT2 in vesicles underlying dendrites, axons, and soma suggests that monoamines may be released at these cellular domains. An understanding of the regulation of transporter function may have important therapeutic consequences for neuroendocrine function in stress and psychiatric disorders.

Amino Acid Sequence↗
PubMed1983

Role of glucose and insulin in the dynamic regulation of glucagon release by the perfused rat pancreas.

The effect of glucose upon the release of glucagon and insulin from the perfused rat pancreas in vitro was studied by varying both the concentration of glucose (from 3.3 to 4.6, 8.5, or 11.1 mmol/l) and the time of exposure to an elevated concentration of the sugar (5, 10 or 23 min). The results suggest that the amount of insulin released during the early period of stimulation could contribute to both the speed and extent of the inhibition in glucagon release. The rate of recovery from inhibition in the A cell, however, appeared to be independent of insulin and was related, in a dose-dependent and time-dependent manner, only to the glucose stimulus. It is suggested that a direct effect of glucose upon the A cell is involved in the physiological regulation of glucagon secretion. An indirect effect of glucose, as mediated via insulin release, may contribute to the rapidity and magnitude of inhibition in A cell secretory activity.

Animals↗
PubMed2006

Adaptations of walking pattern on a compliant surface to regulate dynamic stability.

Dynamic stability can be threatened by various travel surface changes that humans encounter on a daily basis. The central nervous system (CNS) must acquire appropriate information about upcoming surface changes and provide necessary proactive and reactive changes to maintain stability. The purpose of this study was to examine stability control by characterizing adaptations in step patterns, center of mass (COM) trajectory, and lower limb muscle activity when stepping onto and walking on a compliant surface. Eight young adults walked under two conditions: baseline ground walking and while walking on a large foam mat (compliant surface). Optotrak system was used to collect 3D-full body kinematics and electromyography was collected for the rectus femoris, biceps femoris, tibialis anterior, medial gastrocnemius, and soleus bilaterally. Vertical COM decreased on the compliant surface while medio-lateral COM was not affected. This lowering of the vertical COM peak would provide a more stable posture when walking on the surface. Toe trajectory during the swing phase was elevated to avoid tripping on the deformable compliant surface. Step width and length increased on the compliant surface which would increase base of support and provide better control of COM. Increases in gastrocnemius and soleus activity during push-off accounted for increases in step length seen on the compliant surface. Dynamic stability margin in the anterior-posterior direction demonstrated a constant overcompensation and subsequent correction in COM control. These proactive and reactive changes in motor patterns show how the CNS actively coordinates all body segments while traveling on a compliant surface in order to maximize stability.

Adaptation, Physiological↗
PubMed1995

Microfilament dynamics: regulation of actin polymerization by actin-fragmin kinase and phosphatases.

Based on the phosphorylation of the purified actin-fragmin complex, an 80 kDa monomeric kinase (AFK) has been isolated from Physarum polycephalum. Protein chemical analysis and studies involving kinase inhibitors and effectors establish that the AFK is a unique kinase that cannot be classified so far in one of the conventional kinase families. The actin-fragmin kinase behaves as an "independent" kinase since its activity towards the actin-fragmin complex is apparently not regulated by the binding of a ligand (e.g., the cyclic-nucleotides, Ca2+, calmodulin, phosphatidylserine and diolein). Rigorous screening of the substrate specificity suggests that the actin-fragmin complex represents the only substrate for this kinase. This kinase phosphorylates the actin moiety of the actin-fragmin complex at two consecutive threonine residues which constitute one of the contact sites for DNase I (37) and which are also located at one of the proposed actin-actin contact sites along the long-pitch helix of F-actin (38, 39). The physiological importance of this phosphorylation was demonstrated by studying the effect of phosphorylation on the nucleation and the capping activity of the actin-fragmin complex using fluorescence enhancement analysis. As could be demonstrated, the nucleation of actin filaments by the actin-fragmin complex is completely abolished upon phosphorylation by the AFK. Phosphorylation of the complex also interferes with its capping activity, which becomes Ca(2+)-dependent. In addition, capping and nucleating activity is regulated in vitro by phosphoinositides, of which PIP2 displays the highest activity and specificity. PIP2 partially inhibits the nucleation and capping activity of the unphosphorylated actin-fragmin. The capping activity of the phosphorylated actin-fragmin complex was inhibited by PIP2 to a much greater extent as compared to the unphosphorylated actin-fragmin complex. Among all phospholipids tested, PIP2 displayed the highest specificity. Initial experiments with purified preparations of the PP-1, PP-2A, PP-2B, alkaline phosphatase and acid phosphatases showed that PP-1 and PP-2A phosphatases were capable of dephosphorylating the phospho actin-fragmin complex. These findings raised the question of whether these or other protein phosphatases were involved in the dephosphorylation of this substrate in vivo. To address this question, Physarum extracts were subjected to fractionation by ion exchange chromatography, and the column fractions were assayed in a variety of conditions, to identify the protein phosphatases involved in the dephosphorylation of this substrate and to identify the elution position of the major Ser/Thr protein phosphatases present in the Physarum extract.(ABSTRACT TRUNCATED AT 400 WORDS)

Actin Cytoskeleton↗
PubMed2005

Dynamic regulation of hypothalamic neuropeptide gene expression and food intake by melanocortin analogues and reversal with melanocortin-4 receptor antagonist.

Melanocortins are known to be involved in the inhibition of food intake and energy metabolism. Acute and chronic intracerebroventricular administration of several different analogues of alpha-MSH, such as alpha-MSH, NDP-MSH, alpha-MSH-ND, [Gln(6)]alpha-MSH-ND, and [Lys(6)]alpha-MSH-ND, which were substituted in the position of His(6) with Gln and Lys, and cyclic16k-MSH to C57J/BL6 mice resulted in a significant inhibition of both time course food intake and body weight gain, compared to the saline-administered control. However, [Gln(6)]alpha-MSH-ND(6-10), the truncated form of [Gln(6)]alpha-MSH-ND, had no inhibitory effects on food intake. In situ hybridization analysis revealed that the expression levels of AGRP and NPY in the hypothalamus were significantly and rapidly diminished while POMC expression was strongly induced by [Gln(6)]alpha-MSH-ND. Administration of JKC-363, a selective MC4R-specific antagonist, coupled with [Gln(6)]alpha-MSH-ND, specifically reversed the [Gln(6)]alpha-MSH-ND-induced inhibition of food intake, but also reversed the hypothalamic expression levels of neuropeptides such as AGRP, NPY, MCH, and POMC, which suggests [Gln(6)]alpha-MSH-ND can function as a selective MC4R agonist.

Amino Acid Sequence↗