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The Journal of Physiology

Cover image for Vol. 588 Issue 24

December 2010

Volume 588, Issue 24

Pages 4849–5125

  1. PERSPECTIVES

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    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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  2. CLINICAL PERSPECTIVES

    1. Top of page
    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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  3. JOURNAL CLUB

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    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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  4. MOLECULAR AND CELLULAR

    1. Top of page
    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Inflammatory mediators weaken the amniotic membrane barrier through disruption of tight junctions (pages 4859–4869)

      Ken Kobayashi, Hideki Miwa and Masato Yasui

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.197764

      Chorioamnionitis increases the risk of mortality and morbidity in newborn infants because of amniotic fluid infection. However, the mechanism by which this infection crosses the amniotic barrier and spreads into the amniotic fluid remains unclear. In this study, we have shown that inflammation weakens the amniotic barrier and that this effect is induced by inflammatory mediators, such as interleukin-1β, interleukin-6, tumour necrosis factor-α, and prostaglandin E2, in distinctly different ways. Knowledge of the mechanism underlying the weakening of the amniotic barrier aids in increasing our understanding of the mechanism underlying antenatal infection.

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      Epac2-dependent mobilization of intracellular Ca2+ by glucagon-like peptide-1 receptor agonist exendin-4 is disrupted in β-cells of phospholipase C-ɛ knockout mice (pages 4871–4889)

      Igor Dzhura, Oleg G. Chepurny, Grant G. Kelley, Colin A. Leech, Michael W. Roe, Elvira Dzhura, Parisa Afshari, Sundeep Malik, Michael J. Rindler, Xin Xu, Youming Lu, Alan V. Smrcka and George G. Holz

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.198424

      The glucagon-like peptide-1 receptor (GLP-1R) expressed on pancreatic β-cells is the molecular target of a new class of blood glucose-lowering agents designated as the ‘incretin mimetics’. Exendin-4 is an incretin mimetic, and it acts via the GLP-1R to stimulate β-cell insulin secretion, thereby explaining its usefulness as a novel treatment for type 2 diabetes mellitus. Here we report that exendin-4 mobilizes calcium in β-cells, and that this action of exendin-4 is mediated, at least in part, by a phospholipase C-ɛ that is regulated by Epac2 and Rap1, and that was not previously known to exist in β-cells. Our new findings concerning phospholipase C-ɛ provide an unexpected explanation for how GLP-1R agonists act independently of protein kinase A to stimulate calcium-dependent exocytosis of insulin from the β-cells.

      Corrected by:

      Corrigenda

      Vol. 590, Issue 6, 1511, Article first published online: 14 MAR 2012

  5. NEUROSCIENCE

    1. Top of page
    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Boosting brain excitability by transcranial high frequency stimulation in the ripple range (pages 4891–4904)

      Vera Moliadze, Andrea Antal and Walter Paulus

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.196998

      Two distinct populations of high frequency oscillations, called ‘ripples’ (80–200 Hz) and ‘fast ripples’ (250–500 Hz), have been reported in human medial temporal lobe. The frequencies in the ripple range are intensively used in deep brain stimulation for treatment of Parkinson's disease. We showed that 10 min of transcranial alternating current stimulation applied at a peak ripple frequency of 140 Hz increased motor cortex excitability during and for at least an hour after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with delayed induction of excitability and reduced duration. Targeting of cortical ripples may have the potential to manipulate human cortical excitability and to further extend research in the therapeutic application of non-invasive rhythmic brain stimulation.

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      Segmental patterns of vestibular-mediated synaptic inputs to axial and limb motoneurons in the neonatal mouse assessed by optical recording (pages 4905–4925)

      Nedim Kasumacic, Joel C. Glover and Marie-Claude Perreault

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.195644

      Vestibulospinal descending pathways are critical for the regulation of posture and balance. Earlier developmental studies have described the ontogeny and early organization of vestibulospinal projections using purely anatomical methods. Here we use optical techniques for recording the synaptic activation of neurons to show that functional vestibulospinal synaptic connections are already present in the newborn mouse and are organized to differentially regulate activity in neck, axial and limb motoneurons. The organization of these connections includes many of the key features seen in adult mammals. The overall pattern of vestibulospinal inputs we describe may provide an efficient system of postural stabilization suitable to support the complex repertoire of motor behaviours exhibited by the neonate.

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      Regulation of exocytic mode in hippocampal neurons by intra-bouton calcium concentration (pages 4927–4936)

      David A. Richards

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.197509

      The central event in the communication between nerve cells is the fusion of small membrane bound vesicles with the cell membrane, and the release of the neurotransmitter substance (in our case glutamate) into the synapse. Here, we provide data that indicate that the mechanism by which glutamate leaves the vesicle during neurotransmission is modulated by the accumulation of intracellular calcium during stimulus trains. This provides insight into the mechanisms that underpin synaptic transmission, and consequently enhances our understanding of neuronal function.

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      GABAB receptor feedback regulation of bipolar cell transmitter release (pages 4937–4949)

      Yunbo Song and Malcolm M. Slaughter

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.194233

      GABA is an inhibitory neurotransmitter that acts on two classes of receptor: one class opens chloride channels (GABAA and GABAC) and the other activates a biochemical cascade (GABAB). It is well known that GABAA and GABAC receptors are inhibitory at the bipolar cell synapse in the retina. Surprisingly, we found that GABAB receptors enhance bipolar cell synaptic output. In one set of ganglion cells the bipolar cell input is directly enhanced by amacrine cell GABAB feedback. In a different set of ganglion cells, GABAB receptors enhance bipolar cell excitation indirectly by suppressing glycinergic feedback inhibition. Finally, there are a set of bipolar to ganglion cell synapses that are unaffected by GABAB receptor pathways. The results indicate that that there are three discrete circuits between bipolar cells and ganglion cells.

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      Properties of urethral rhabdosphincter motoneurons and their regulation by noradrenaline (pages 4951–4967)

      Koji Yashiro, Karl B. Thor and Edward C. Burgard

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.197319

      The urethral rhabdosphincter is a specialized muscle that helps maintain urinary continence by preventing urine leakage from the bladder during events such as coughing, laughing and sneezing. We show that the neurotransmitter noradrenaline has excitatory effects on a specific group of spinal motoneurons that control the activity of this muscle. These findings improve our understanding of the physiological control of urinary continence and may help guide the search for new drug treatments for incontinence.

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      Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel (pages 4969–4985)

      Arthur Beyder, James L. Rae, Cheryl Bernard, Peter R. Strege, Frederick Sachs and Gianrico Farrugia

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.199034

      The heart, gastrointestinal tract and skeletal muscle are examples of electromechanical systems – excitable tissues with mechanical function. In such systems, mechano-electrical feedback is a process by which mechanical stimuli affect electrical performance. Electrical excitability of electromechanical systems is mediated by voltage-gated ion channels. These are proteins that are embedded in cell membranes and conduct ions in response to voltage shifts. In this study, we examined the effects of mechanical stretch on performance of a voltage gated sodium selective ion channel (Nav1.5) found in the heart and gut. Stretch had effects on various functional aspects of these channels. We showed that stretch increased peak sodium current, shifted the voltage dependence of activation and channel availability, and stabilized inactivation. These findings suggest the involvement of Nav1.5 in mechano-electrical feedback.

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      Post-tetanic potentiation is caused by two signalling mechanisms affecting quantal size and quantal content (pages 4987–4994)

      Lei Xue and Ling-Gang Wu

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.196964

      High-frequency firings induce post-tetanic potentiation (PTP) of transmission at synapses that influence neuronal circuit function. PTP is in part due to protein kinase C (PKC) activation that increases the number of released vesicles. We recently found that PTP is paralleled by an increased quantal size of spontaneous release, the response to individual vesicle release, which, according to quantal analysis, suggests that PTP is also caused by the quantal size increase. This suggestion is somewhat undermined by recent suggestion that spontaneous and evoked release originate from different vesicle pools. Furthermore, whether the quantal size increase is mediated by PKC is unclear. Here we reported that PTP was caused by increases of the released vesicle number and quantal size, which were PKC-dependent and -independent, respectively. We verified the assumption of quantal analysis – same mechanism controls the quantal size of spontaneous and evoked release, which supports the use of quantal analysis at synapses.

  6. CARDIOVASCULAR

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    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Hydrogen ion dynamics in human red blood cells (pages 4995–5014)

      Pawel Swietach, Teresa Tiffert, Jakob M. A. Mauritz, Rachel Seear, Alessandro Esposito, Clemens F. Kaminski, Virgilio L. Lew and Richard D. Vaughan-Jones

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.197392

      Red blood cells are essential for the transport of oxygen and carbon dioxide around the body. Their ability to carry these gases depends strongly on intracellular pH (acid-base balance). Using a pH-sensitive dye, we were able to study, for the first time, dynamic changes of pH inside individual red blood cells. Using this approach, we have characterised the physiological mechanisms that regulate red blood cell pH in response to acid/base disturbances. Proteins, called anion exchangers, swap bicarbonate (HCO3) for chloride anions across the cell membrane. These regulate the cell's pH. We show that the activity of these proteins underlies an important link between pH and cell volume, which has previously been predicted to occur in sickle-cell disease. We have extended our measurement system to sample pH from a large population of cells. These measurements will be useful for studying pH-related phenomena that occur in healthy or diseased red blood cells.

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      Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy (pages 5015–5032)

      Kai-Chien Yang, Nicholas C. Foeger, Céline Marionneau, Patrick Y. Jay, Julie R. McMullen and Jeanne M. Nerbonne

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.197418

      Cardiac hypertrophy is an adaptive response of the heart to increased pressure or volume, and is observed in a variety of cardiac diseases, including in individuals with high blood pressure and/or who have recently experienced a heart attack. This pathological hypertrophy is associated with marked changes in the electrical properties of the heart, predisposing afflicted individuals to life threatening cardiac arrhythmias. Interestingly, hypertrophy is also observed with exercise, particularly in trained athletes, and, in contrast with pathological hypertrophy, physiological hypertrophy is not associated with increased arrhythmia risk. The results presented here demonstrate that ion channel expression is upregulated with exercise and with the activation of metabolic signalling pathways normally triggered by exercise to maintain the normal electrical functioning of the myocardium. These observations suggest that activation of the pathways triggered in physiological hypertrophy may provide a novel therapeutic strategy to reduce or prevent arrhythmias in patients with pathological hypertrophy.

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      Alteration in skeletal muscle afferents in rats with chronic heart failure (pages 5033–5047)

      Han-Jun Wang, Yu-Long Li, Lie Gao, Irving H. Zucker and Wei Wang

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.199562

      An exaggerated exercise pressor reflex (EPR) can cause exercise intolerance and excessive sympatho-excitation in the chronic heart failure (CHF) state. However, the components of this reflex that are responsible for the exaggerated EPR in CHF remain unknown. To answer this question, we examined muscle afferent function in sham-operated and CHF rats. We also investigated the roles of purinergic 2X receptor (P2X) and the transient receptor potential vanilloid 1 (VR1) in mediating the altered sensitivity of muscle afferents. We found that compared to sham rats, group III afferents are sensitized whereas group IV afferents are desensitized in CHF rats, which appears to be related to the dysfunction of P2X and VR1 receptors. Our findings provide a potential therapeutic target for exercise intolerance in this disease.

  7. ALIMENTARY

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    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
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    10. INTEGRATIVE
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      Loss of PDZ-adaptor protein NHERF2 affects membrane localization and cGMP- and [Ca2+]- but not cAMP-dependent regulation of Na+/H+ exchanger 3 in murine intestine (pages 5049–5063)

      Mingmin Chen, Ayesha Sultan, Ayhan Cinar, Sunil Yeruva, Brigitte Riederer, Anurag Kumar Singh, Junhua Li, Janina Bonhagen, Gang Chen, Chris Yun, Mark Donowitz, Boris Hogema, Hugo deJonge and Ursula Seidler

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.198721

      During digestion, the distal intestine needs to reabsorb large quantities of salt and water that have been secreted into the gastrointestinal lumen by more proximal organs or are ingested through the mouth. We here show that the major salt absorptive transporter, sodium/hydrogen exchanger isoform 3 (NHE3), requires the PDZ-adaptor protein NHERF2 to determine its localization along the terminal web-microvillar axis in the apical pole of the enterocyte. The NHERF-2 deficient murine intestine has also lost the ability of certain secretagogues to inhibit NHE3 absorptive function and thereby to cause diarrhoea. NHERF-2 is therefore an important regulator of intestinal fluid transport, and is an interesting drug target, encoded by a potential disease-causing modifier gene.

  8. SKELETAL MUSCLE AND EXERCISE

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    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
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    10. INTEGRATIVE
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      Effects of acidification and increased extracellular potassium on dynamic muscle contractions in isolated rat muscles (pages 5065–5076)

      Kristian Overgaard, Grith Westergaard Højfeldt and Ole Bækgaard Nielsen

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.195727

      During intense dynamic exercise, fatigue may develop causing the muscle to lose force and speed and, thus, generate less power. This occurs whilst potassium ions (K+) and lactic acid accumulate in the working muscle. We investigated the effects of acidification and high extracellular K+ concentration ([K+]o), either alone or in combination, on the ability of a muscle to develop power. Our study shows that both increased extracellular [K+]o and severe acidification are detrimental to dynamic contractile function in muscles. However when the muscle is exposed to high [K+]o while simultaneously exposed to reduced pH, acidification exerts a positive effect protecting the muscle against K+-induced loss of dynamic contractile function. These findings may improve our understanding of the mechanisms behind peripheral muscle fatigue.

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      Critical speed in the rat: implications for hindlimb muscle blood flow distribution and fibre recruitment (pages 5077–5087)

      Steven W. Copp, Daniel M. Hirai, Timothy I. Musch and David C. Poole

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.198382

      Exercise above critical speed (CS) imparts distinct, poorly understood physiological challenges culminating in rapid exhaustion. The rat is an established model for examining physiological underpinnings of exercise performance; however, until now, CS had not been investigated in this species. Here we determined CS in the rat and validated its metabolic (whole-body O2 consumption and blood [lactate]) and performance (time to exhaustion) implications during constant-speed tests above and below CS. Additionally, hindlimb skeletal muscle blood flow measurements revealed that predominantly glycolytic muscle regions are recruited to the greatest extent above, relative to below, CS. These data establish an important platform for future CS investigations in this model and advance our understanding of the mechanisms responsible for the global metabolic and performance implications of CS.

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      Effects of inactivity on human muscle glutathione synthesis by a double-tracer and single-biopsy approach (pages 5089–5104)

      Francesco Agostini, Luciano Dalla Libera, Jörn Rittweger, Sara Mazzucco, Mihaela Jurdana, Igor B. Mekjavic, Rado Pišot, Luisa Gorza, Marco Narici and Gianni Biolo

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.198283

      Evidence in animals suggests that during inactivity oxidative stress could induce muscle atrophy through enhancement of reactive oxygen species and deregulation of antioxidant systems. We showed that glutathione availability and protein oxidative stress markers were enhanced in atrophying muscles. Increases of protein oxidation were directly related to increases of muscle atrophy induced by inactivity. Thus, in the present work we show that muscle oxidative stress is associated to wasting processes after a long term period of inactivity. Glutathione kinetic upregulation, assessed by a newly validated method, was considered as a response to an increase in oxidative stress. This suggests that glutathione can potentially counteract inactivity mediated muscle atrophy.

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      Force-generating capacity of human myosin isoforms extracted from single muscle fibre segments (pages 5105–5114)

      Meishan Li and Lars Larsson

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.199067

      Myosin is the molecular motor protein in skeletal muscle that generates force and movement. It is expressed in multiple isoforms that have different enzymatic properties. There are isoform specific differences in contractile speed, but there is no consensus if the force generating capacity differs between isoforms. In this study we have modified a single fibre in vitro motility assay to measure both force and speed generated by specific myosin isoforms extracted from short single human muscle fibre segments. It is shown that human slow myosin is weaker and slower than fast myosin. This assay is put forward as a useful tool for future investigations on myosin function in response to modifications associated with muscle disease or ageing.

  9. INTEGRATIVE

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    2. PERSPECTIVES
    3. CLINICAL PERSPECTIVES
    4. JOURNAL CLUB
    5. MOLECULAR AND CELLULAR
    6. NEUROSCIENCE
    7. CARDIOVASCULAR
    8. ALIMENTARY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Effects of maternal hypoxia on muscle vasodilatation evoked by acute systemic hypoxia in adult rat offspring: changed roles of adenosine and A1 receptors (pages 5115–5125)

      Andrew M. Coney and Janice M. Marshall

      Article first published online: 15 DEC 2010 | DOI: 10.1113/jphysiol.2010.198275

      An adverse environment for the fetus during pregnancy is known to be associated cardiovascular disease in adult life. Two of the main components in making a healthy environment for the developing fetus are a sufficient supply of both nutrients and oxygen. We have investigated the effect of decreasing oxygen levels before birth. In normal adult rats, a reduction in blood oxygen induces vasodilatation (relaxation of blood vessels) in skeletal muscle that is partly caused by adenosine. We have now shown that when blood oxygen is reduced in adult rats, which were exposed to low oxygen before birth, this induces vasodilatation, but it is not mediated by adenosine. The cells that release adenosine, in this situation, line the blood vessels (the endothelium). Endothelial dysfunction has been implicated in cardiovascular diseases. Thus, these results suggest that inadequate oxygen in pregnancy may lead to cardiovascular disease.

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