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The Journal of Physiology

Cover image for Vol. 588 Issue 15

August 2010

Volume 588, Issue 15

Pages 1–2972

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Issue Information (pages 1–6)

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.58815

  2. PERSPECTIVES

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Exercise: not just a medicine for muscle? (pages 2687–2688)

      John P. Thyfault and R. Scott Rector

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.193797

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      Realistic cardiac electrophysiology modelling: are we just a heartbeat away? (page 2689)

      Elizabeth M. Cherry and Flavio H. Fenton

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.194357

  3. MOLECULAR AND CELLULAR

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Quinidine interaction with Shab K+ channels: pore block and irreversible collapse of the K+ conductance (pages 2691–2706)

      Froylan Gomez-Lagunas

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.193128

      Quinidine is a drug commonly used in clinical cardiology as an antiarrhythmic agent. In this work the mechanism of quinidine inhibition of Shab potassium channels is reported. In particular it is shown that, on blocking Shab, quinidine interacts with pore K+ ions, and as a result of this interaction when the drug blocks Shab in an external solution lacking K+ ions, the channels irreversibly sink into a state in which they are unable to conduct ions, despite the presence of a physiological K+ concentration in the intracellular solution. It appears that when Shab channels are open the pore conformation able to conduct is stable in the absence of K+, but on channel deactivation (closing) this conformation collapses.

  4. NEUROSCIENCE

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Patterns of expiratory and inspiratory activation for thoracic motoneurones in the anaesthetized and the decerebrate rat (pages 2707–2729)

      Anoushka T. R. De Almeida, Sarah Al-Izki, Manuel Enríquez Denton and Peter A. Kirkwood

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.192518

      The operation of the neural circuits in the brainstem that control breathing are only partly understood. In recent years these circuits have been shown to contain two separate oscillators. One drives inspiration. The role of the other is controversial, though in some studies in newborn animals it appears to drive expiration. Here we present evidence that in adult animals the operation of this second oscillator can still be detected, driving the activity of expiratory muscles. The pattern of the expiratory and inspiratory activity among the different thoracic muscles in the rat is also seen to be unusual, as compared to other species. A fuller description of these patterns will allow a better understanding of the mechanical actions of respiratory muscles, which can be compromised in various disease states.

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      Multiple phases of excitation and inhibition in central respiratory drive potentials of thoracic motoneurones in the rat (pages 2731–2744)

      Anoushka T. R. De Almeida and Peter A. Kirkwood

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2009.186346

      There are a variety of rhythmical movements, such as respiration or locomotion, that are controlled automatically by neural circuits in the spinal cord or brainstem. The output neurones of these circuits, which contact muscles directly, the motoneurones, have most often been described as being alternately excited and inhibited in order to produce the required rhythmical pattern. We show that for the thoracic muscles of the rat, some motoneurones are excited in both phases of respiration. Further, some of these motoneurones are simultaneously excited and inhibited during inspiration. This new variation in the patterns of excitation and inhibition helps reveal the neural mechanisms involved in the control of such rhythmic movements.

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      Sprouting capacity of lumbar motoneurons in normal and hemisected spinal cords of the rat (pages 2745–2768)

      T. Gordon and N. Tyreman

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.190389

      Motor nerves each supply many muscle cells within a skeletal muscle. Injury to some of these nerves, as occurs at the level of spinal cord injury, leaves some muscle cells without nerves. Remaining intact nerves branch (sprout) to re-supply these denervated muscle cells. In rats, we used physiological and anatomical techniques to demonstrate that after partial removal of nerve supply (1) there is an upper limit ∼4-fold increase in numbers of muscle fibres supplied by sprouting nerves and (2) this limit is not changed after spinal cord injury. Spatial analysis of the muscle cells indicated that remaining motor nerves branch to supply nearby muscle cells distributed amongst muscle cells with intact nerve supply. We conclude that sprouting has an upper limit that relates to the territorial distribution of the muscle cells supplied by single nerves and also that reduced neuromuscular activity, unlike eliminated activity, does not reduce sprouting capacity.

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      Fast activation of feedforward inhibitory neurons from thalamic input and its relevance to the regulation of spike sequences in the barrel cortex (pages 2769–2787)

      Fumitaka Kimura, Chiaki Itami, Koji Ikezoe, Hiroshi Tamura, Ichiro Fujita, Yuchio Yanagawa, Kunihiko Obata and Minoru Ohshima

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.188177

      Sensory information enters the cerebral cortex through the thalamus, first arriving at layer 4 (L4), where synapses are changed, and then reaching layer 2/3 (L2/3). Here we show that in mice thalamic inputs to L4 activate inhibitory neurons slightly earlier than excitatory neurons through axons with higher conduction velocity specifically targeting inhibitory neurons. Such preceding activation of inhibitory neurons, occurring only after the end of the second postnatal week, is likely to serve to establish sequenced activation of ‘L4 leading L2/3’ cells by generating precisely timed fast feedforward inhibition on both L4 and L2/3 neurons. Since the spiking order of L4 and L2/3 neurons determines the direction and the strength of the changes in synaptic connections at these synapses, our findings provide an important clue to the understanding of the mechanism of information processing and plasticity during the critical period in the cerebral cortex.

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      The illusion of changed position and movement from vibrating one arm is altered by vision or movement of the other arm (pages 2789–2800)

      Masahiko Izumizaki, Mikio Tsuge, Lena Akai, Uwe Proske and Ikuo Homma

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.192336

      In a forearm position matching task where the right, reference arm was always hidden from view, position errors during blindfolded matching were compared with errors when subjects could see their left arm, its mirror image, or matching used a dummy arm. Matching accuracy did not change for the three conditions compared with blindfolded matching, but when the right arm was vibrated, the illusion of elbow extension was significantly reduced when subjects viewed the mirror image or the dummy. In a second experiment, the perceived speed of extension of the vibrated arm could be slowed down or sped up by moving the other arm into extension or flexion respectively. These experiments demonstrate an interdependence of proprioceptive sensations in the two arms.

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      Two distinct and activity-dependent mechanisms contribute to autoreceptor-mediated inhibition of GABAergic afferents to hilar mossy cells (pages 2801–2822)

      Casie Lindsly and Charles J. Frazier

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2009.184648

      Central cholinergic systems are likely to play an important role in learning and memory-related behaviours, and their degradation has been heavily implicated in geriatric memory dysfunction. However, when studied at a detailed mechanistic level, the effects of cholinergic compounds on brain physiology are remarkably complex. This study provides a detailed mechanistic explanation for how a single cholinergic agonist can produce apparently disparate effects on inhibitory synaptic transmission in an area of the brain that is important for memory formation and heavily implicated in the aetiology of temporal lobe epilepsy. Through this work, we ultimately discovered an intriguing and unexpected feature of inhibitory synapses in this area. Specifically, we find these synapses are capable of regulating their own activity through two distinct and activity-dependent mechanisms. This finding raises an intriguing question about whether future therapeutic strategies might be able to selectively target, or effectively mimic, high activity conditions.

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      Development of calcium-permeable AMPA receptors and their correlation with NMDA receptors in fast-spiking interneurons of rat prefrontal cortex (pages 2823–2838)

      Huai-Xing Wang and Wen-Jun Gao

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.187591

      Abnormal influx of calcium contributes to the neuronal injury in a number of brain disorders. Calcium-permeable AMPA receptors (CP-AMPARs) play a critical role in the pathological process. We found that most of the inhibitory fast-spiking (FS) interneurons in the prefrontal cortex exhibit CP-AMPARs. These cells demonstrate many distinct physiological properties, including few or no NMDA receptors and prominent frequency-dependent short-term facilitation. The CP-AMPA receptors also exhibit dramatic changes during cortical development with a significant decrease in rectification index and an increase in paired-pulse facilitation during adolescence. These data suggest that CP-AMPARs may make FS interneurons particularly vulnerable to disruptive influences in the prefrontal cortex, thus contributing to the onset of many psychiatric disorders.

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      Intraspinally mediated state-dependent enhancement of motoneurone excitability during fictive scratch in the adult decerebrate cat (pages 2839–2857)

      Kevin E. Power, David A. McCrea and Brent Fedirchuk

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.188722

      To generate movements, cells in the spinal cord (motoneurones) send a signal through the nerve to the muscle for contraction. The excitability of motoneurones measured ‘at rest’ changes when a movement is initiated, such that their excitability is increased, thus ensuring their activation and the ensuing muscle contraction. It is known that input to motoneurones from higher nervous system structures are important in modulating motoneurone excitability during movement. We show that mechanisms located within the spinal cord also increase motoneurone excitability during movement, independent of input from higher structures. Knowledge of how the spinal cord regulates motoneurone excitability during movement is essential for the development of strategies used to facilitate functional recovery of the nervous system following disease or injury.

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      Distinctive properties of CXC chemokine receptor 4-expressing Cajal–Retzius cells versus GABAergic interneurons of the postnatal hippocampus (pages 2859–2878)

      Ivan Marchionni, Virág T. Takács, Maria Grazia Nunzi, Enrico Mugnaini, Richard J. Miller and Gianmaria Maccaferri

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.190868

      Chemokines are a class of molecules that regulate cellular functions by binding to specific receptors on the surface of the cells. Although several types of chemokines and their receptors are expressed in the postnatal brain, many of their functions remain unknown. Here, we have characterized the role of a specific chemokine named SDF-1 α in a specific area of the brain, the stratum lacunosum-moleculare of the hippocampus. We show that SDF-1 α dramatically reduces the spontaneous activity of a specific neuronal type, the Cajal–Retzius cell, but does not affect the activity of different neurons in the same area. We propose that reducing spontaneous activity of Cajal–Reztius cells has important implications for the functions of the local network. We also propose that pathological conditions associated with increased levels of this chemokine may broadly impact the physiological functions of the hippocampal stratum lacunosum-moleculare.

  5. CARDIOVASCULAR

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Atrial natriuretic peptide inhibits angiotensin II-stimulated proliferation in fetal cardiomyocytes (pages 2879–2889)

      P. F. O’Tierney, N. N. Chattergoon, S. Louey, G. D. Giraud and K. L. Thornburg

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.191098

      Atrial natriuretic peptide (ANP) plays an important role in regulating blood pressure and heart growth in adult mammals. It is not known how ANP affects heart growth in the fetus, though ANP levels are very high at this stage of development. We show here that ANP inhibits fetal heart cell proliferation in sheep following stimulation by a growth factor, angiotensin II (Ang II). ANP blocks the downstream cell growth signalling pathways stimulated by Ang II. These data are important because heart cell numbers are determined in the perinatal period and have lifelong consequences for cardiovascular health.

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      Length dependence of force generation exhibit similarities between rat cardiac myocytes and skeletal muscle fibres (pages 2891–2903)

      Laurin M. Hanft and Kerry S. McDonald

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.190504

      The Frank–Starling Law of the heart states that the greater the volume of blood in a ventricle of the heart at the end of diastole, the greater the volume ejected during ventricular contraction. The cellular basis of this is the length–tension relationship of the ventricular myocytes. This study shows, for the first time, that there are two distinct populations of length–tension relationships in left ventricular cardiac myocytes, one steep like fast-twitch skeletal muscle fibres and the other shallow like slow-twitch skeletal muscle fibres. Cardiac myocytes with shallow length–tension relationships can be converted to steep relationships by protein kinase A (PKA)-induced myofilament phosphorylation. These findings help explain how β-adrenergic stimulation, which acts via PKA, leads to greater stroke volume.

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      Regulation of myocyte contraction via neuronal nitric oxide synthase: role of ryanodine receptor S-nitrosylation (pages 2905–2917)

      Honglan Wang, Serge Viatchenko-Karpinski, Junhui Sun, Inna Györke, Nancy A. Benkusky, Mark J. Kohr, Héctor H. Valdivia, Elizabeth Murphy, Sandor Györke and Mark T. Ziolo

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.192617

      Nitric oxide (NO) is an important regulator of cardiac contraction. NO produced via the neuronal isoform of NO synthase (NOS1) leads to enhanced contraction. We show that part of the enhanced contraction via NOS1 is through the modulation of the sarcoplasmic reticulum Ca2+ release channel (ryanodine receptor). Specifically, we find that NOS1 leads to S-nitrosylation and increased activity of the ryanodine receptor. We further show that the increased ryanodine receptor activity by NOS1 contributes to the enhanced contraction. These results reveal a mechanism of how NOS1 modulates cardiac contraction and helps us understand how NO influences cardiac function.

  6. ALIMENTARY

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Colonic elongation inhibits pellet propulsion and migrating motor complexes in the murine large bowel (pages 2919–2934)

      Dante J. Heredia, Eamonn J. Dickson, Peter O. Bayguinov, Grant W. Hennig and Terence K. Smith

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.191445

      The migrating motor complex (CMMC) is a rhythmic, electrical and contractile motor pattern (rather than a simple reflex) that normally propagates in an oral to anal direction along the colon, transporting the contents of the colon slowly distally. In this study we have examined how it is affected by colonic elongation (longitudinal stretch). Using a mouse model, we demonstrate that colonic elongation occurs naturally in the colon when it fills with faecal pellets. Colonic elongation activates interneurons within the colonic wall that release the gas nitric oxide to reduce both pellet propulsion and the amplitude of CMMCs by inhibiting activity in myenteric neurons that generate the CMMC. The mechanisms underlying and regulating the CMMC are important clinically since many patients with severe slow transit constipation have CMMCs that propagate in a reverse direction, as well as an elongated colon.

  7. RESPIRATORY

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
    1. RAPID REPORT

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      Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle (pages 2935–2944)

      Aihua Li and Eugene Nattie

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.191288

      Orexin, a small protein made exclusively in neurons located within the hypothalamus, helps the body decide when to be awake and facilitates many physiological processes during wakefulness. A drug, almorexant, that blocks the receptors at which orexin acts has recently been shown to promote sleep. In this study we show that it also reduces the breathing response to increased CO2 and decreases the frequency of spontaneous deep breaths or sighs, which are important in keeping small air passages open, effects that were more prominent in wakefulness in the active period of the diurnal cycle. Orexin is important in the processes that regulate breathing by detecting changes in CO2 and by modulating reflexes that maintain normal lung function.

  8. SKELETAL MUSCLE AND EXERCISE

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      In vivo expression of G-protein β1γ2 dimer in adult mouse skeletal muscle alters L-type calcium current and excitation–contraction coupling (pages 2945–2960)

      Norbert Weiss, Claude Legrand, Sandrine Pouvreau, Hicham Bichraoui, Bruno Allard, Gerald W. Zamponi, Michel De Waard and Vincent Jacquemond

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.191593

      Contraction of voluntary skeletal muscles relies on the functional coupling between a voltage-sensing Ca2+ channel in the plasma membrane of the muscle cells (the dihydropyridine receptor) and another Ca2+ channel (the ryanodine receptor) that releases Ca2+ from an intracellular store into the cytoplasm to activate contraction. There is very limited insight as to whether G-protein-coupled receptors (GPCRs) signalling could modulate this process. We show that expression of a given G-protein βγ signalling complex in adult muscle fibres reduces both the plasma membrane Ca2+ channel function and Ca2+ release from the intracellular store. Results open up the intriguing possibility that excitation–contraction coupling could be regulated through this G-protein-dependent mechanism. Finding the ligand and associated GPCR that could power it is the next exciting challenge.

  9. INTEGRATIVE

    1. Top of page
    2. Issue Information
    3. PERSPECTIVES
    4. MOLECULAR AND CELLULAR
    5. NEUROSCIENCE
    6. CARDIOVASCULAR
    7. ALIMENTARY
    8. RESPIRATORY
    9. SKELETAL MUSCLE AND EXERCISE
    10. INTEGRATIVE
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      Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to β-adrenergic stimulation (pages 2961–2972)

      Jennifer C. Richards, Tyler K. Johnson, Jessica N. Kuzma, Mark C. Lonac, Melani M. Schweder, Wyatt F. Voyles and Christopher Bell

      Version of Record online: 3 AUG 2010 | DOI: 10.1113/jphysiol.2010.189886

      Very high-intensity, sprint-like interval exercise training (SIT) and traditional endurance exercise training elicit similar adaptations. From the perspective of metabolic control, common characteristics of endurance-trained adults include superior regulation of blood sugar and responsiveness to insulin (the hormone primarily responsible for transporting sugar from blood and into tissues). Accordingly, we investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active people. Thirty one healthy adults were assigned to one of three conditions: (1) SIT (12 people): six sessions of repeated (4–7) 30 s bouts of very high-intensity cycle exercise over 14 days; (2) sedentary control (no exercise; 10 people); (3) single-bout SIT (9 people): one session of 4 × 30 s cycle ergometer sprints. Compared with baseline, and sedentary and single-bout controls, SIT increased insulin sensitivity. Sixteen minutes of high-intensity sprint-like exercise spread over 14 days improves the control of blood glucose in previously sedentary/recreationally active adults.

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