bluuebunny/crossref_metadata_2025 huggingface dataset:
Phagosomal acidification: measurement, manipulation and functional consequences
Authors: Steinberg B.E. , Huynh K.K. , Grinstein S.
Published: November 2007

Phagocytosis holds a central position in the development of a successful innate immune response and in the initiation of the corresponding adaptive response. The destruction of invading pathogens and the presentation of their antigens to lymphoid cells require acidification of the phagosomal lumen. The present review discusses the mechanism of phagosome acidification, with particular reference to the two components of the protonmotive force: the chemical (pH) gradient and the electrical potential across the phagosomal membrane. A method for the in situ measurement of the electrical potential across the phagosomal membrane is described. In addition, we discuss the finding that acidification is not only a consequence, but also a critical determinant of phagosome maturation. Luminal acidification appears to function as a timing device controlling the transition between early and late phagosomes.
The V-ATPase a2-subunit as a putative endosomal pH-sensor
Authors: Marshansky V.
Published: November 2007

V-ATPase (vesicular H+-ATPase)-driven intravesicular acidification is crucial for vesicular trafficking. Defects in vesicular acidification and trafficking have recently been recognized as essential determinants of various human diseases. An important role of endosomal acidification in receptor–ligand dissociation and in activation of lysosomal hydrolytic enzymes is well established. However, the molecular mechanisms by which luminal pH information is transmitted to the cytosolic small GTPases that control trafficking events such as budding, coat formation and fusion are unknown. Here, we discuss our recent discovery that endosomal V-ATPase is a pH-sensor regulating the degradative pathway. According to our model, V-ATPase is responsible for: (i) the generation of a pH gradient between vesicular membranes; (ii) sensing of intravesicular pH; and (iii) transmitting this information to the cytosolic side of the membrane. We also propose the hypothetical molecular mechanism involved in function of the V-ATPase a2-subunit as a putative pH-sensor. Based on extensive experimental evidence on the crucial role of histidine residues in the function of PSPs (pH-sensing proteins) in eukaryotic cells, we hypothesize that pH-sensitive histidine residues within the intra-endosomal loops and/or C-terminal luminal tail of the a2-subunit could also be involved in the pH-sensing function of V-ATPase. However, in order to identify putative pH-sensitive histidine residues and to test this hypothesis, it is absolutely essential that we increase our understanding of the folding and transmembrane topology of the a-subunit isoforms of V-ATPase. Thus the crucial role of intra-endosomal histidine residues in pH-dependent conformational changes of the V-ATPase a2-isoform, its interaction with cytosolic small GTPases and ultimately in its acidification-dependent regulation of the endosomal/lysosomal protein degradative pathway remain to be determined.
The function of the NADPH oxidase of phagocytes, and its relationship to other NOXs
Authors: Behe P. , Segal A.W.
Published: November 2007

The NADPH oxidase of ‘professional’ phagocytic cells transfers electrons across the wall of the phagocytic vacuole, forming superoxide in the lumen. It is generally accepted that this system promotes microbial killing through the generation of reactive oxygen species and through the activity of myeloperoxidase. An alternative scenario exists in which the passage of electrons across the membrane alters the pH and generates a charge that drives ions into, and out of, the vacuole. It is proposed that the primary function of the oxidase is to produce these pH changes and ion fluxes, and the issues surrounding these processes are considered in this review. The neutrophil oxidase is the prototype of a whole family of NOXs (NAPDH oxidases) that exist throughout biology, from plants to humans, which might function, at least in part, in a similar fashion.
Defining a role for platelets in allergic inflammation
Authors: Pitchford S.C.
Published: November 2007

There is now considerable evidence suggesting a role for platelets as inflammatory cells. These actions are distinct from their classically known actions performed during thrombosis and haemostasis, and include the expression of adhesion molecules and contact-dependent activation of leucocytes, the release of a plethora of inflammatory mediators, activation in cells of the adaptive immune response and the ability to migrate and undergo chemotaxis. Chronic asthma is a disease characterized by a mixed inflammatory cell pulmonary infiltrate, AHR (airways hyper-responsiveness) and tissue remodelling. Clinical data from patients suffering from asthma, allergic rhinitis and allergic dermatitis reveal changes in platelet behaviour and function during or after allergen exposure. Furthermore, mouse models of allergic inflammation demonstrate a role for intact platelets in eosinophil and lymphocyte recruitment to the lungs, a mechanism that is P-selectin (platelet selectin)-dependent. Models of chronic inflammation also reveal the participation of platelets in tissue remodelling events whereby platelet depletion was found to be more effective in suppressing airway remodelling processes than the administration of a glucocorticosteroid. This process of destruction and repair to the architecture of airway tissue is therefore perhaps enhanced by platelet activation. Recent evidence demonstrates that platelets can undergo chemotaxis and indicates an ability to migrate through inflamed tissue, where they localize to specific tissue sites. Indeed, platelets have been shown to become activated and recruited to various body compartments in direct response to allergen via IgE and this is suggestive of a link between the innate and adaptive immune responses. Thus these actions may lead to pathophysiological events that alter disease progression, since platelet depletion suppresses AHR in allergic rabbits. Further investigations into the role of platelets in inflammation may be beneficial in the search for future therapeutic targets in the treatment of asthma and allergy.
Lymphocyte cell motility: the twisting, turning tale of phosphoinositide 3-kinase
Authors: Oak J.S. , Matheu M.P. , Parker I. , Cahalan M.D. , Fruman D.A.
Published: November 2007

The PI3K (phosphoinositide 3-kinase) family of lipid kinases regulate cell motility in diverse organisms and cell types. In mammals, the main PI3K enzyme activated by chemokine receptor signalling is the class IB isoform, p110γ. Studies of p110γ-knockout mice have shown an essential function for this isoform in chemotaxis of neutrophils and macrophages both in vitro and in vivo. However, the roles of p110γ and other PI3K enzymes and regulatory subunits in lymphocyte motility have been more difficult to discern. Recent studies of adoptively transferred, fluorescently labelled lymphocytes have revealed complex and unexpected functions for PI3K in lymphocyte migration in vivo. In this review we highlight cell-type-specific roles for PI3K catalytic and regulatory subunits in the homing and basal motility of lymphocytes in the intact lymph node.
Interleukin-1 and inflammatory neurodegeneration
Authors: Simi A. , Tsakiri N. , Wang P. , Rothwell N.J.
Published: November 2007

Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time, for example in Alzheimer's or Parkinson's diseases and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration under these conditions, and that the cytokine IL-1 (interleukin-1) is a pivotal mediator. IL-1 is expressed rapidly in response to neuronal injury, predominantly by microglia, and elevated levels of endogenous or exogenous IL-1 markedly exacerbate injury. The naturally occurring IL-1RA (IL-1 receptor antagonist) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS (central nervous system) invasion, and cell death via activation of matrix metalloproteinase-9. IL-1 also influences the release of toxins from glial and endothelial cells. Neuronal responses to excitotoxins and physiological factors may have an impact on neuronal survival. IL-1RA, delivered peripherally, can enter the CNS in animals and humans and has no adverse effects in stroke or subarachnoid haemorrhage patients, but shows potential benefit in acute stroke patients.
Chronic microglial activation and progressive dopaminergic neurotoxicity
Authors: Block M.L. , Hong J.-S.
Published: November 2007

PD (Parkinson's disease) is characterized by the selective and progressive loss of DA neurons (dopaminergic neurons) in the substantia nigra. Inflammation and activation of microglia, the resident innate immune cell in the brain, have been strongly linked to neurodegenerative diseases, such as PD. Microglia can respond to immunological stimuli and neuronal death to produce a host of toxic factors, including cytokines and ROS (reactive oxygen species). Microglia can also become persistently activated after a single stimulus and maintain the elevated production of both cytokines and ROS, long after the instigating stimulus is gone. Current reports suggest that this chronic microglial activation may be fuelled by either dying/damaged neurons or autocrine and paracrine signals from local glial cells, such as cytokines. Here, we review proposed mechanisms responsible for chronic neuroinflammation and explain the interconnected relationship between deleterious microglial activation, DA neuron damage and neurodegenerative disease.
Nitric oxide, ischaemia and brain inflammation
Authors: Murphy S. , Gibson C.L.
Published: November 2007

Cerebral ischaemia results in the activation of three isoforms of NOS (nitric oxide synthase) that contribute to the development of and recovery from stroke pathology. This review discusses, in particular, the role of the transcriptionally activated NOS-2 (inducible NOS) isoform and summarizes the outcomes of experimental stroke studies with regard to the therapeutic utility of nitric oxide donors and NOS inhibitors.
Carbon monoxide-releasing molecules (CO-RMs): vasodilatory, anti-ischaemic and anti-inflammatory activities
Authors: Motterlini R.
Published: November 2007

The well-known adverse effects of CO (carbon monoxide) intoxication are counterbalanced by its positive actions when small amounts are produced intracellularly by the cytoprotective enzyme HO-1 (haem oxygenase-1). As compelling scientific evidence accumulated to sustain that HO-1 plays a fundamental role in counteracting vascular and inflammatory disorders, we began to appreciate that a controlled delivery of CO to mammals may provide therapeutic benefits in a number of pathological states. This is the rationale for the recent development of CO-RMs (CO-releasing molecules), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, which offer a plausible tool for studying the pharmacological effects of this gas and identifying its mechanism(s) of action. The present review will highlight the encouraging results obtained so far on the vasodilatory, anti-ischaemic and anti-inflammatory effects elicited by CO-RMs in in vitro and in vivo models with an emphasis on the prospect of converting chemical CO carriers into CO-based pharmaceuticals.
Redox regulation of lung inflammation: role of NADPH oxidase and NF-κB signalling
Authors: Yao H. , Yang S.-R. , Kode A. , Rajendrasozhan S. , Caito S. , Adenuga D. , Henry R. , Edirisinghe I. , Rahman I.
Published: November 2007

Regulation of reduction/oxidation (redox) state is critical for cell viability, activation, proliferation and organ function, and imbalance of oxidant/antioxidant balance is implicated in various chronic respiratory inflammatory diseases, such as asthma, pulmonary fibrosis and chronic obstructive pulmonary disease. CS (cigarette smoke) is a complex mixture of various noxious gases and condensed tar particles. These components elicit oxidative stress in lungs by continuous generation of ROS (reactive oxygen species) and various inflammatory mediators. In the present review, we have discussed the role of oxidative stress in triggering the inflammatory response in the lungs in response to CS by demonstrating the role of NADPH oxidase, redox-sensitive transcription factors, such as pro-inflammatory NF-κB (nuclear factor κB) and antioxidant Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), as well as HDAC (histone deacetylase) in pro-inflammatory cytokine release by disruption of HDAC–RelA/p65 NF-κB complex.
Modulation of endothelial responses by the stromal microenvironment: effects on leucocyte recruitment
Authors: McGettrick H.M. , Filer A. , Rainger G.E. , Buckley C.D. , Nash G.B.
Published: November 2007

Vascular endothelial cells play a pivotal role in regulating leucocyte recruitment during inflammation, and their responses can be modulated by their local environment, including cells of the tissue stroma. We have developed a model system to examine how the communication between endothelial cells and fibroblasts regulates the recruitment of leucocytes and their subsequent subendothelial fate. Here, we describe a novel co-culture filter-based flow assay and highlight the ability of synovial fibroblasts obtained from chronically inflamed tissue to promote leucocyte recruitment to otherwise ‘resting’ endothelial cells.
P2X7 receptor-mediated reactive oxygen and nitrogen species formation: from receptor to generators
Authors: Hewinson J. , MacKenzie A.B.
Published: November 2007

RONS (reactive oxygen and nitrogen species) have traditionally been perceived to be detrimental to the physiology of the cell, with reports citing mechanisms by which a range of proteins, lipids and DNA are damaged. Consequently, their action has been attributed to many pathologies and the aging process. Opposing these actions are the protective functions held by RONS, as highlighted in microbial destruction, and their role as important cellular signalling molecules. The present paper will focus on the newly emerging field of P2X7R (P2X7 receptor)-induced RONS generation and the current understanding of the signalling pathways from receptor to RONS generators.
Amino acid metabolism, insulin secretion and diabetes
Authors: Newsholme P. , Bender K. , Kiely A. , Brennan L.
Published: November 2007

In addition to the primary stimulus of glucose, specific amino acids may acutely and chronically regulate insulin secretion from pancreatic β-cells in vivo and in vitro. Mitochondrial metabolism is crucial for the coupling of glucose, alanine, glutamine and glutamate recognition with exocytosis of insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP (the main coupling messenger in insulin secretion) and other factors that serve as sensors for the control of the exocytotic process. The main factors that mediate the key amplifying pathway over the Ca2+ signal in nutrient-stimulated insulin secretion are nucleotides (ATP, GTP, cAMP and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. In addition, after chronic exposure, specific amino acids may influence gene expression in the β-cell, which have an impact on insulin secretion and cellular integrity. Therefore amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion.
Amino acids and mTOR signalling in anabolic function
Authors: Proud C.G.
Published: November 2007

Amino acids regulate signalling through the mTORC1 (mammalian target of rapamycin, complex 1) and thereby control a number of components of the translational machinery, including initiation and elongation factors. mTORC1 also positively regulates other anabolic processes, in particular ribosome biogenesis. The most effective single amino acid is leucine. A key issue is how intracellular amino acids regulate mTORC1. This does not require the TSC1/2 (tuberous sclerosis complex 1/2) complex, which is involved in the activation of mTORC1, for example, by insulin. Progress in understanding the mechanisms responsible for this will be reviewed.
Intestinal glucose sensing and regulation of intestinal glucose absorption
Authors: Dyer J. , Daly K. , Salmon K.S.H. , Arora D.K. , Kokrashvili Z. , Margolskee R.F. , Shirazi-Beechey S.P.
Published: November 2007

SGLT1 (Na+/glucose co-transporter 1) transports the dietary sugars, D-glucose and D-galactose, from the lumen of the intestine into enterocytes. SGLT1 regulation has important consequences for the provision of glucose to the respiring tissues and is therefore essential for maintaining glucose homoeostasis. SGLT1 expression is directly regulated in response to changes in the sugar content of the diet. To monitor these variations, there is a requirement for a glucose-sensing system located on the luminal membrane of gut cells. This short review focuses on recent findings on intestinal sugar sensing and the downstream mechanisms responsible for enhancement in SGLT1 expression.
Physiological significance of L-amino acid sensing by extracellular Ca2+-sensing receptors
Authors: Conigrave A.D. , Mun H.-C. , Brennan S.C.
Published: November 2007

The calcium-sensing receptor is a multimodal, multimetabolic sensor that mediates the feedback-dependent control of whole body calcium metabolism. Remarkably, in addition to its role in Ca2+o (extracellular Ca2+) sensing, the CaR (Ca2+-sensing receptor) also responds to L-amino acids. L-amino acids appear to activate, predominantly, a signalling pathway coupled with intracellular Ca2+ mobilization, require a threshold concentration of Ca2+o for efficacy and sensitize the receptor to activation by Ca2+o. Here, we review the evidence that the CaR, like other closely related members of the class 3 GPCR (G-protein-coupled receptor) family including GPRC6A, is a broad-spectrum amino acid-sensing receptor, consider the nature of the signalling response to amino acids and discuss its physiological significance.
PERK in the life and death of the pancreatic β-cell
Authors: Herbert T.P.
Published: November 2007

To ensure cellular survival to ER (endoplasmic reticulum) stress, PERK [PKR (double-stranded-RNA-dependent protein kinase)-like ER kinase], an ER transmembrane kinase, is activated as part of the unfolded protein response. PERK is highly expressed in pancreatic β-cells and is essential in the β-cell's development, differentiation and function. However, chronic activation of PERK can induce cell death, and its activation has been implicated in both Type 1 and Type 2 diabetes. This short review aims to provide an insight into our current understanding of the role of PERK in the life and death of the β-cell.
Glucokinase activators: molecular tools for studying the physiology of insulin-secreting cells
Authors: Johnson D. , Shepherd R.M. , Gill D. , Gorman T. , Smith D.M. , Dunne M.J.
Published: November 2007

GK (glucokinase) catalyses the phosphorylation of glucose to glucose 6-phosphate in glucosensitive cells. In pancreatic β-cells, this reaction is the rate-limiting step of insulin release. Recent work has led to the discovery of synthetic small-molecule activators of GK that stimulate β-cell physiology and subsequently enhance the glucose-dependent release of insulin. It is currently recognized that these compounds may represent a significant advance in the development of new agents in the treatment of diabetes. In addition, GKAs (GK activators) are emerging as reagents that are useful tools with which to probe the function of pancreatic β-cells and other glucosensitive cells. This includes providing insights into the physiology of the β-cell by helping to elucidate the kinetic cycle of GK, confirming the central role of glucose metabolism to the β-cell and highlighting subtle species-dependent differences in insulin secretion between rodent and human islets of Langerhans.
Retinoic acid-mediated transcription and maturation of SREBP-1c regulates fatty acid synthase via cis-elements responsible for nutritional regulation
Authors: Roder K. , Schweizer M.
Published: November 2007

A region of the rat FAS (fatty acid synthase) promoter has been defined as being responsible for RA (retinoic acid) responsiveness. The defined promoter region is devoid of canonical RA-response elements but contains cis-elements binding generalized and specific transcription factors that mediate the dietary response of FAS. Our results are consistent with SREBP-1c (sterol-regulatory-element-binding protein 1c) binding in this region, thus bringing about the RA responsiveness of the rat FAS proximal promoter.
Amino acid transporters and nutrient-sensing mechanisms: new targets for treating insulin-linked disorders?
Authors: Reynolds B. , Laynes R. , Ögmundsdóttir M.H. , Boyd C.A.R. , Goberdhan D.C.I.
Published: November 2007

The IIS (insulin/IGF (insulin-like growth factor) signalling) cascade has an important role in regulating normal development and physiology, as evidenced by its effects in a host of major human diseases including cancer, Type 2 diabetes and neurodegeneration. Recently, it has become clear that multiple types of local nutrient-sensing mechanisms have an impact on cellular insulin-sensitivity through the downstream kinase TOR (target of rapamycin). In vivo analysis in flies has surprisingly highlighted PATs (proton-assisted amino acid transporters) as having a uniquely potent role in regulating IIS/TOR activity and growth, potentially via a novel signalling mechanism. Other molecules such as the heterodimeric amino acid transporter, CD98, which provides the principal route for cellular uptake of leucine, an amino acid implicated in regulating TOR, also appear to have important effects. As our understanding of how nutrient sensing has an impact on IIS/TOR increases, novel targets to modulate aberrant IIS in disease are likely to emerge, which could complement current strategies designed to block kinases in this pathway.
Linking glycolysis with oxidative stress in neural cells: a regulatory role for nitric oxide
Authors: Bolaños J.P. , Herrero-Mendez A. , Fernandez-Fernandez S. , Almeida A.
Published: November 2007

NO (nitric oxide) participates in a considerable number of physiological functions. At the biochemical level, most of its actions can be ascribed to its ability to bind, and activate, soluble guanylate cyclase. However, mounting evidence now strongly suggests that the NO-mediated inhibition of cytochrome c oxidase, the terminal complex of the mitochondrial respiratory chain, may be a further step of a cell signalling process involved in the regulation of important cellular functions. In most cells, including neurons and astrocytes, NO reversibly, and irreversibly, modulates O2 consumption, a phenomenon through which NO signals certain pathways relevant for neuronal survival. Here, we propose that besides the control of mitochondrial bioenergetics, NO finely modulates the balance between glucose consumption through the glycolytic pathway and the pentose phosphate pathway in neurons. This may have implications for our understanding of the mechanisms of neurodegeneration due to oxidative and nitrosative stress.
Mitochondrial dysfunction in neurodegenerative disorders
Authors: Baron M. , Kudin A.P. , Kunz W.S.
Published: November 2007

There is compelling evidence for the direct involvement of mitochondria in certain neurodegenerative disorders, such as Morbus Parkinson, FRDA (Friedreich's ataxia), ALS (amyotrophic lateral sclerosis), and temporal lobe epilepsy with Ammon's horn sclerosis. This evidence includes the direct genetic evidence of pathogenic mutations in mitochondrial proteins in inherited Parkinsonism {such as PARK6, with mutations in the mitochondrial PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1]} and in FRDA (with mutations in the mitochondrial protein frataxin). Moreover, there is functional evidence of impairment of the respiratory chain in sporadic forms of Parkinsonism, ALS, and temporal lobe epilepsy with Ammon's horn sclerosis. In the sporadic forms of the above-mentioned neurodegenerative disorders, increased oxidative stress appears to be the crucial initiating event that affects respiratory chain function and starts a vicious cycle finally leading to neuronal cell death. We suggest that the critical factor that determines the survival of neurons in neurodegenerative disorders is the degree of mitochondrial DNA damage and the maintenance of an appropriate mitochondrial DNA copy number. Evidence for a depletion of intact copies of the mitochondrial genome has been provided in all above-mentioned neurodegenerative disorders including ALS and temporal lobe epilepsy with Ammon's horn sclerosis. In the present study, we critically review the available data.
Do mitochondrial DNA mutations have a role in neurodegenerative disease?
Authors: Krishnan K.J. , Reeve A.K. , Turnbull D.M.
Published: November 2007

A decline in mitochondrial function has long been shown to exist in neurodegenerative disease. Whether this decline is a secondary consequence of other factors or whether it causes the eventual death of a cell is unknown. In this review, we will discuss some of the major evidence surrounding mitochondrial DNA mutations leading to mitochondrial dysfunction in neurodegenerative disease and discuss their possible role in neurodegeneration.
Somatodendritic dynorphin release: orchestrating activity patterns of vasopressin neurons
Authors: Brown C.H. , Scott V. , Ludwig M. , Leng G. , Bourque C.W.
Published: November 2007

Most neurons in the central nervous system co-express peptides alongside their principal transmitter, yet the function of these peptides is largely unknown. Vasopressin neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus contain among the highest concentrations of dynorphin found in the brain. Dynorphin, an endogenous opioid peptide, is co-localized in the same neurosecretory vesicles as vasopressin and is released alongside vasopressin from the dendrites and axon terminals of vasopressin neurons. We and others have shown that neuropeptide release from the soma and dendrites of vasopressin neurons activates vasopressin receptors and κ-opioid receptors to cause activity-dependent modulation of vasopressin neuron activity, and that this is essential for activity patterning in vasopressin neurons.
The actin filament and dendritic peptide release
Authors: Tobin V.A. , Ludwig M.
Published: November 2007

F-actin remodelling has been implicated in regulated secretion from many cell types, in particular secretion from neuron axon terminals and neuroendocrine cell types. Cortical F-actin has long been postulated to act as a barrier to vesicle movement and hence to inhibit secretion; however, more recent studies point to F-actin remodelling providing both supporting and restraining roles in secretion. Magnocellular neurons of the supraoptic nucleus secrete either oxytocin or vasopressin from their dendrites as well as their axon terminals; and peptide release from these two compartments can be differentially controlled to allow secretion from one compartment in isolation from the other. While oxytocin and vasopressin secretion can be provoked by F-actin depolymerization in both compartments, acutely stimulated secretion is dependent on F-actin remodelling in dendrites but not axon terminals, suggesting that F-actin plays a different role in regulating the readily releasable pool of secretory vesicles in the two compartments. In addition, activity-dependent secretion from the dendritic compartment can be primed by prior exposure to agents, including oxytocin, that stimulate release of Ca2+ from intracellular stores. While remodelling of F-actin is involved, it is not solely responsible for priming secretory responses.
Central release of oxytocin and the ventromedial hypothalamus
Authors: Sabatier N. , Rowe I. , Leng G.
Published: November 2007

Recent studies on the regulation of social behaviours by neuropeptides indicate that it is the distribution of peptide receptor expression in particular brain areas that determines the specificity of peptide actions; and that, accordingly, peptides can evoke specific behaviours when administered centrally without temporal or spatial selectivity of administration. The release of neuropeptides at synaptic sites appears irrelevant, and in the brain, some peptides are released mainly from dendrites rather than from nerve endings. Dendritic peptide release can be long lasting, semi-independent of electrical activity, and allows the diffusion of peptides to distant targets. The peptide oxytocin regulates many behaviours; in particular, it inhibits food intake. Centrally, oxytocin is released in large amounts by the dendrites of hypothalamic magnocellular neurons. This mini-review considers the possible involvement of dendritically released oxytocin in the regulation of food intake by its actions on the ventromedial hypothalamus.
Stimuli and consequences of dendritic release of oxytocin within the brain
Authors: Neumann I.D.
Published: November 2007

The brain oxytocin system has served as a distinguished model system in neuroendocrinology to study detailed mechanisms of intracerebral release, in particular of somatodendritic release, and its behavioural and neuroendocrine consequences. It has been shown that oxytocin is released within various brain regions, but evidence for dendritic release is limited to the main sites of oxytocin synthesis, i.e. the hypothalamic SON (supraoptic nucleus) and PVN (paraventricular nucleus). In the present paper, stimuli of dendritic release of oxytocin and the related neuropeptide vasopressin are discussed, including parturition and suckling, i.e. the period of a highly activated brain oxytocin system. Also, exposure to various pharmacological, psychological or physical stressors triggers dendritic oxytocin release, as monitored by intracerebral microdialysis within the SON and PVN during ongoing behavioural testing. So far, dendritic release of the neuropeptide has only been demonstrated within the hypothalamus, but intracerebral oxytocin release has also been found within the central amygdala and the septum in response to various stimuli including stressor exposure. Such a locally released oxytocin modulates physiological and behavioural reproductive functions, emotionality and hormonal stress responses, as it exerts, for example, pro-social, anxiolytic and antistress actions within restricted brain regions. These discoveries make oxytocin a promising neuromodulator of the brain for psychotherapeutic intervention and treatment of numerous psychiatric illnesses, for example, anxiety-related diseases, social phobia, autism and postpartum depression.
Nitric oxide and respiratory rhythm in mammals: a new modulator of phase transition?
Authors: Pierrefiche O. , Abdala A.P.L. , Paton J.F.R.
Published: November 2007

NO (nitric oxide) modulates several central pattern generators, but its role in respiratory rhythmogenesis and its mode of action on medullary respiratory neurons during normoxia are unknown. We analysed the actions of NO on the mammalian respiratory network at the system and cellular levels. Given systemically, the NO donor diethylamine NONOate increased post-inspiratory duration in vagus, phrenic and hypoglossal nerves, whereas blockade of NO generation with L-NAME (NG-nitro-L-arginine methyl ester) produced the opposite response. At the cellular level, we pressure-ejected the NO donor on to respiratory neurons. NO had both inhibitory and excitatory effects on all types of respiratory neurons. Inhibitory effects involved soluble guanylate cyclase, as they were blocked with ODQ (1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one), whereas excitations were antagonized by uric acid and possibly mediated via peroxynitrite. Importantly, NO facilitated both GABA (γ-aminobutyric acid)- and NMDA (N-methyl-D-aspartate)-induced neuronal responses, but this was restricted to post-inspiratory and pre-inspiratory neurons; other neuron types showed additive effects only. Our results support NO as modulator of centrally generated respiratory activity and specifically of ligand-mediated responses in respiratory neuron types involved in respiratory phase transition.
Physiological and pathophysiological roles of extracellular ATP in chemosensory control of breathing
Authors: Ackland G.L. , Kasymov V. , Gourine A.V.
Published: November 2007

The purine nucleotide ATP mediates several distinct forms of sensory transduction in both the peripheral and central nervous systems. These processes share common mechanisms that involve the release of ATP to activate ionotropic P2X and/or metabotropic P2Y receptors. Extracellular ATP signalling plays an important role in ventilatory control, mediating both peripheral and central chemosensory transduction to changes in arterial levels of oxygen and carbon dioxide. New data also suggest that extracellular ATP may play an important role in mediating certain neurophysiological responses to systemic inflammation. Here, we propose the novel concept that both peripheral and central neurophysiological effects of ATP may contribute to alterations in ventilatory control during inflammatory pathophysiological states.
Respiratory plasticity following intermittent hypoxia: roles of protein phosphatases and reactive oxygen species
Authors: Wilkerson J.E.R. , MacFarlane P.M. , Hoffman M.S. , Mitchell G.S.
Published: November 2007

Plasticity is an important property of the respiratory control system. One of the best-studied models of respiratory plasticity is pLTF (phrenic long-term facilitation). pLTF is a progressive increase in phrenic motor output lasting several hours following acute exposure to intermittent hypoxia. Similar to many other forms of neuroplasticity, pLTF is pattern-sensitive; it is induced by intermittent, but not sustained hypoxia of similar cumulative duration. Our understanding of the cellular/synaptic mechanisms underlying pLTF has increased considerably in recent years. Here, we review accumulating evidence suggesting that the pattern-sensitivity of pLTF arises substantially from differential reactive oxygen species formation and subsequent protein phosphatase inhibition during intermittent compared with sustained hypoxia in or near phrenic motor neurons. A detailed understanding of the cellular/synaptic mechanisms of pLTF may provide the rationale for new pharmacological approaches in the treatment of severe ventilatory control disorders, such as obstructive sleep apnoea and respiratory insufficiency either following spinal cord injury or during neurodegenerative diseases such as amyotrophic lateral sclerosis.
Regulation of cAMP by the p75 neurotrophin receptor: insight into drug design of selective phosphodiesterase inhibitors
Authors: Sachs B.D. , Akassoglou K.
Published: November 2007

Subcellular compartmentalization of PDEs (phosphodiesterases) is a major mechanism for the regulation of cAMP signalling. The identification of the proteins that recruit specific PDE isoforms to subcellular compartments can shed light on the regulation of spatial and temporal cAMP gradients in living cells and provide novel therapeutic targets for inhibiting functions of PDEs. We showed recently that p75NTR (p75 neurotrophin receptor) interacts directly with a single PDE isoform, namely PDE4A4/5, via binding to its unique C-terminal region, and targets cAMP degradation to the membrane. The purpose of this review is to present the biological significance of PDE4A compartmentalization by p75NTR and discuss the potential of inhibiting the interaction between p75NTR and PDE4A for the development of an isoform-specific inhihibitor for PDEs.
Liprin-α proteins: scaffold molecules for synapse maturation
Authors: Spangler S.A. , Hoogenraad C.C.
Published: November 2007

Synapses are specialized communication junctions between neurons whose plasticity provides the structural and functional basis for information processing and storage in the brain. Recent biochemical, genetic and imaging studies in diverse model systems are beginning to reveal the molecular mechanisms by which synaptic vesicles, ion channels, receptors and other synaptic components assemble to make a functional synapse. Recent evidence has shown that the formation and function of synapses are critically regulated by the liprin-α family of scaffolding proteins. The liprin-αs have been implicated in pre- and post-synaptic development by recruiting synaptic proteins and regulating synaptic cargo transport. Here, we will summarize the diversity of liprin binding partners, highlight the factors that control the function of liprin-αs at the synapse and discuss how liprin-α family proteins regulate synapse formation and synaptic transmission.
Dissecting DISC1 function through protein–protein interactions
Authors: Brandon N.J.
Published: November 2007

Disrupted in schizophrenia 1 (DISC1) is emerging in the eyes of many as the most promising candidate of all the schizophrenia risk genes. This viewpoint is derived from the combination of genetic, clinical, imaging and rapidly advancing cell biology data around this gene. All of these areas have been reviewed extensively recently and this review will point you towards some of these excellent papers. My own personal view of the potential importance of DISC1 was echoed in a recent review which suggested that DISC1 may be a ‘Rosetta Stone’ for schizophrenia research [Ross, Margolis, Reading, Pletnikov and Coyle (2006) Neuron 52, 139–153]. Our own efforts to try to understand the function of DISC1 were through identification of its protein-binding partners. Through an extensive Y2H (yeast two-hybrid) and bioinformatics effort we generated the ‘DISC1-Interactome’, a comprehensive network of protein–protein interactions around DISC1. In two excellent industry–academia collaborations we focused on two main interacting partners: Ndel1 (nudE nuclear distribution gene E homologue-like 1), an enigmatic protein which may have diverse functions as both a cysteine protease and a key centrosomal structural protein; and PDE4B, a cAMP-specific phosphodiesterase. I will review the work around these two protein complexes in detail.
Neurotoxicity of tryptophan metabolites
Authors: Smith A.J. , Stone T.W. , Smith R.A.
Published: November 2007

The metabolism of tryptophan by the kynurenine pathway leads to the production of several neurotoxic compounds, some of which have been associated with neurological disorders. Recent investigation of some relevant compounds in this pathway has provided further evidence of their neurotoxicity.
Interaction of integrin β1 with cytokeratin 1 in neuroblastoma NMB7 cells
Authors: Chuang N.-N. , Huang C.-C.
Published: November 2007

Cytokeratin 1, an intermediate filament keratin, was isolated as a partner of the tyrosine kinase Src from neuroblastoma NMB7 cells. The cytokeratin 1–Src complex was found to be associated with the molecular scaffolder RACK1 (receptor for activated protein kinase C). Interestingly, the cytokeratin 1–Src–RACK1 complex was found to actively bind with membrane receptors such as integrin β1. We are interested in using this complex to find downstream kinases and phosphatases that bind upon cytokine stimulation, especially during neurogenesis.
IL-6 signalling in exercise and disease
Authors: Pedersen B.K.
Published: November 2007

Low-grade chronic inflammation is a feature of Type 2 diabetes and appears to play a pathogenetic role in insulin resistance. It is well known that cytokines, besides their immunoregulatory roles, are important players in metabolism. Moreover, it has become evident that skeletal muscles express several cytokines, which belong to distinct cytokine classes. IL-6 (interleukin-6) is a pleiotropic cytokine produced by virtually all multinucleated cells including skeletal myocytes where it is produced in response to contraction. IL-6 is subsequently released into the circulation, where it works in a hormone-like fashion to induce lipolysis and fat oxidation. In more recent experiments, it has been shown that IL-6 infusion increases glucose disposal during a hyperinsulinaemic euglycaemic clamp in healthy humans. IL-6 treatment of myotubes increases fatty acid oxidation, basal and insulin-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increases AMPK (AMP-activated protein kinase) and the metabolic effects of IL-6 were abrogated in AMPK dominant negative-infected cells. Finally, IL-6 mediates anti-inflammatory effects by stimulating the production of anti-inflammatory cytokines and by suppressing TNFα (tumour necrosis factor α) production. We suggest that IL-6 and other muscle-derived cytokines (myokines) may play a role in defending Type 2 diabetes.
The role of nutrition in stimulating muscle protein accretion at the molecular level
Authors: Kimball S.R.
Published: November 2007

Nutrients act both directly and indirectly to modulate muscle protein accretion through changes in protein synthesis and degradation. For example, glucose, amino acids and fatty acids can all be metabolized to produce energy in the form of ATP that can be utilized for protein synthesis. In addition, amino acids are used directly for the synthesis of new proteins. Nutrients also regulate protein synthesis through activation of a signalling pathway involving the protein kinase, mTOR [mammalian TOR (target of rapamycin)]. Together with several regulatory proteins, mTOR forms a complex referred to as TORC1 (TOR complex 1). Because of its central role in controlling cell growth, TORC1 is an integral component of the mechanism through which nutrients modulate protein synthesis. Herein, the mechanism(s) through which nutrients, and in particular amino acids, regulate signalling through TORC1 will be discussed. In addition, downstream effectors of TORC1 action on mRNA translation will be briefly presented. Finally, a previously unrecognized effector of TORC1 signalling in regulating protein synthesis will be described.
Exercise- and nutrient-controlled mechanisms involved in maintenance of the musculoskeletal mass
Authors: Rennie M.J.
Published: November 2007

The mechanisms of maintenance of the protein mass of muscle and associated connective tissue and bone are becoming more accessible as a result of the use of a combination of well-established techniques for measurement of protein turnover and measurement of protein expression and phosphorylation state of signalling molecules involved in anabolic and catabolic responses. Amino acids, hormones and physical activity appear to be the major short-term physiological regulators of muscle mass, mainly through their actions on protein synthesis and breakdown, on a time scale of minutes to hours, with duration of changes in gene expression up to weeks. Amino acids are the main components in the diet regulating protein turnover, having marked effects in stimulating muscle protein synthesis and with almost no effect on muscle protein breakdown. Branched-chain amino acids, and in particular leucine, simulate protein synthesis via signalling pathways involving mTOR (mammalian target of rapamycin) in a dose–response manner. Insulin has little effect on protein synthesis in human muscle, but it has a marked inhibitory effect on protein breakdown. The amino acid simulation of anabolism is not dependent on the presence of insulin, IGF-1 (insulin-like growth factor-1) or growth hormone. Exercise not only stimulates protein synthesis in muscle, but also in tendon; and disuse atrophy is accompanied by marked decreases of both muscle and tendon collagen protein synthesis. Bone collagen synthesis appears to be nutritionally regulated by the availability of amino acids, but not lipid or glucose.
Mechanotransduction in striated muscle via focal adhesion kinase
Authors: Durieux A.C. , Desplanches D. , Freyssenet D. , Flück M.
Published: November 2007

Contractile tissues demonstrate a pronounced capacity to remodel their composition in response to mechanical challenges. Descriptive evidence suggests the upstream involvement of the phosphotransfer enzyme FAK (focal adhesion kinase) in the molecular control of load-dependent muscle plasticity. Thereby FAK evolves as a myocellular transducer of mechanical signals towards downstream transcript expression in myofibres. Recent advances in somatic gene therapy now allow the exploration of the functional involvement of this enzyme in mechanotransduction in intact muscle.
Tuberculosis: evolution in millennia and minutes
Authors: Gillespie S.H.
Published: November 2007

Tuberculosis remains a global public health threat: the causative organism, Mycobacterium tuberculosis, was once thought to show little genetic variation, but research in the last 10 years has demonstrated an ability to change in a series of different time frames. Related species of mycobacteria have undergone evolution by deletion of segments of DNA, allowing Mycobacterium bovis and other species to emerge from the M. tuberculosis complex, disproving the previously accepted theories. Deletions also affect the pathogenic potential of different lineages of M. tuberculosis. Over shorter time periods genetic variation is achieved by the movement of insertion sequences such as IS6110. Some lineages identified by this means are over-represented in patient populations, suggesting a genetic advantage, although the mechanism for this is not yet apparent. M. tuberculosis must also adapt to host and antibiotic selection pressure, and this is achieved by point mutations. Almost all antibiotic resistance emerges in this way, and data from clinical and in vitro studies indicate that M. tuberculosis exists with pre-existent mutants that remain as a small proportion of the population because of fitness deficits. Under certain physiological conditions, these rarer mutants may be favoured and, when antibiotic selection pressure is applied, will rise to dominate the bacterial population. M. tuberculosis is a highly effective pathogen that has caused disease in human populations for millennia. We are now starting to understand some of the genetic mechanisms behind this phenomenon.
Structure, function and biosynthesis of the Mycobacterium tuberculosis cell wall: arabinogalactan and lipoarabinomannan assembly with a view to discovering new drug targets
Authors: Alderwick L.J. , Birch H.L. , Mishra A.K. , Eggeling L. , Besra G.S.
Published: November 2007

In spite of effective antibiotics to treat TB (tuberculosis) since the early 1960s, we enter the new millennium with TB, currently the leading cause of death from a single infectious agent, killing more than three million people worldwide each year. Thus an understanding of drug-resistance mechanisms, the immunobiology of cell wall components to elucidate host–pathogen interactions and the discovery of new drug targets are now required for the treatment of TB. Above the plasma membrane is a classical chemotype IV PG (peptidoglycan) to which is attached the macromolecular structure, mycolyl-arabinogalactan, via a unique diglycosylphosphoryl bridge. This review will discuss the assembly of the mAGP (mycolyl-arabinogalactan-peptidoglycan), its associated glycolipids and the site of action of EMB (ethambutol), bringing forward a new era in TB research and focus on new drugs to combat multidrug resistant TB.