The Journal of Physiology (J PHYSIOL-LONDON)

Publications in this journal

• Article: The role of endogenous molecules in modulating pain through TRPV1

  Sara L Morales-Lázaro, Sidney A. Simon, Tamara Rosenbaum
  [show abstract] [hide abstract]
  ABSTRACT: Pain is a physiological response to a noxious stimulus that decreases the quality of life of people who suffer from it. Research aimed at finding new therapeutic targets for the treatment of several maladies including pain has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1, a member of the Transient Receptor Potential (TRP) family of ion channels. TRPV1 is a calcium permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, irritant and pungent compounds and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 while, in contrast, other lipids produced in response to tissue injury and ischemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules such as divalent cations have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.
  The Journal of Physiology 04/2013;
• Article: The role of endogenous molecules in modulating pain through TRPV1

  Sara L Morales-Lázaro, Sidney A. Simon, Tamara Rosenbaum
  [show abstract] [hide abstract]
  ABSTRACT: Pain is a physiological response to a noxious stimulus that decreases the quality of life of people who suffer from it. Research aimed at finding new therapeutic targets for the treatment of several maladies including pain has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1, a member of the Transient Receptor Potential (TRP) family of ion channels. TRPV1 is a calcium permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, irritant and pungent compounds and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 while, in contrast, other lipids produced in response to tissue injury and ischemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules such as divalent cations have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.
  The Journal of Physiology 04/2013;
• Article: CrossTalk opposing view: Forward and backward pressure waves in the arterial system do not represent reality

  J.V. Tyberg, J.C. Bouwmeester, N.G. Shrive, J.J. Wang
  The Journal of Physiology 03/2013; 591(5):1171.
• Article: Ethnic differences in autonomic tone and heat adaptation during intensive exercise in English Premiership Footballers training in extreme heat.

  J. Dalzell, A. K. Datta
  [show abstract] [hide abstract]
  ABSTRACT: Athletic performance may be compromised in extreme heat; this was relevant for the Athens and Beijing Olympics and may be for the 2014 and 2022 FIFA World cups in Brazil and Qatar respectively; under those conditions prior determination of required fluid intake is vital for athlete safety. Thompson (1954) described lower sweating rates in Bantus compared with Caucasians. The three aims of the study are: first, to determine the ethnic mix of the English Football Premiership. Second, to establish the fluid intake, sweat production and sweat evaporation during exercise in extreme heat. Third, to determine whether there are ethnic differences in the above and to establish the cardiorespiratory and other physiological factors contributing to any putative ethnic differences. Using Scout 7 software, we analysed all 270 English Football Premiership footballers in 2009; 44% players were of African origin (AO) and 56% of European origin (EO). Heart rate variability (HRV) was calculated from a five minute collection of resting ECG using bespoke frequency domain analysis software using American Heart Association guidelines (Omega Wave; Oregon USA). The ratio of Low frequency power (LF; 0.04 to 0.15 Hz) to High frequency power (HF; 0.15 to 0.40 Hz) i.e. LF/HF ratio, an index of sympatho-vagal tone balance, was calculated for all players. Mean + SD LF/HF ratio was 1.07 + 0.48 in AO, significantly lower than in EO (2.0 + 1.27; p= 0.03; unpaired t-test). Studies were performed in United Arab Emirates after four days heat acclimation, during 80 minutes training at 40 ± 2°C ambient temperature; 25 ± 8% relative humidity on 21 professional Premiership footballers from a single team with Ethics clearance. 12 were AO and 9 EO. Players could drink ad libitum throughout. AO and EO subjects exercised to a similar degree as evidenced by heart rates (Polar Electro). There was no difference between AO and EO in height, weight, body surface area, skin fold thickness, resting or average heart rate, electrocardiographically measured QT interval, echocardiographically measured cardiac chamber dimensions, left ventricular ejection fraction or maximum VO2. During exercise, fluid intake in AO ranged from 1.2- 3.0L (1.8 + 0.63L, median + SD) and in EO ranged from 0.5-1.9L (1.2 + 0.51L ; p=0.055; unpaired t-test). Sweat production in AO ranged from 1.8 - 3.9L (2.3+ 0.56L) compared with 1.3 - 2.7L in EO (2.09 + 0.48L; p = 0.09). We conclude that fluid intake during exercise in extreme heat may be up to 2.25 L/hr. There may be an increased sweat production in AO players which would confer a performance advantage to exercising in the heat and that this appears to be associated with an increased sympathetic tone, which has also been related to an increased risk of cardiac events (Tsuji H et al ,1996) .
  The Journal of Physiology 01/2012; 27:PC106.
• Article: Beyond muscular effects: depression of spinal recurrent inhibition after botulinum neurotoxin A.Marchand-Pauvert V, Aymard C, Giboin LS, Dominici F, Rossi A, Mazzocchio R.J Physiol. 2012 Oct 8. [Epub ahead of print]PMID: 23045348 [PubMed - as supplied by publisher]

  Marchand-Pauvert V, Aymard C, Giboin LS, Dominici F, Rossi A, Mazzocchio R
  The Journal of Physiology 01/2012;
• Article: Preinspiratory calcium rise in putative pre-Bötzinger complex astrocytes

  Okada Y, Sasaki T, Oku Y, Takahashi N, Seki M, Ujita S, Tanaka KF, Matsuki N, Ikegaya Y
  The Journal of Physiology 01/2012; 590(19):4933-4944.
• Article: Does a lack of RyR3 make mammalian skeletal muscle EC coupling a 'spark-less' affair?

  Chris W Ward, George G Rodney
  The Journal of Physiology 02/2008; 586(2):313-4.
• Article: Orai1 subunit stoichiometry of the mammalian CRAC channel pore.

  Olivier Mignen, Jill L Thompson, Trevor J Shuttleworth
  [show abstract] [hide abstract]
  ABSTRACT: Agonist-activated Ca2+ entry plays a critical role in Ca2+ signalling in non-excitable cells. One mode of such entry is activated as a consequence of the depletion of intracellular Ca2+ stores. This depletion is sensed by the protein STIM1 in the endoplasmic reticulum, which then translocates to regions close to the plasma membrane where it induces the activation of store-operated conductances. The most thoroughly studied of these conductances are the Ca2+ release-activated Ca2+ (CRAC) channels, and recent studies have identified the protein Orai1 as comprising the essential pore-forming subunit of these channels. Although evidence suggests that Orai1 can assemble as homomultimers, whether this assembly is necessary for the formation of functional CRAC channels and, if so, their relevant stoichiometry is unknown. To examine this, we have used an approach involving the expression of preassembled tandem Orai1 multimers comprising different numbers of subunits into cells stably overexpressing STIM1, followed by the recording of maximally activated CRAC channel currents. In each case, any necessity for recruitment of additional Orai1 units to these preassembled multimers in order to form functional channels was evaluated by coexpression with a dominant-negative Orai1 mutant. In this way we were able to demonstrate, for the first time, that the functional CRAC channel pore is formed by a tetrameric assembly of Orai1 subunits.
  The Journal of Physiology 02/2008; 586(2):419-25.
• Article: Natriuretic peptide C receptor signalling in the heart and vasculature.

  Robert A Rose, Wayne R Giles
  [show abstract] [hide abstract]
  ABSTRACT: Natriuretic peptides (NPs), including atrial, brain and C-type natriuretic peptides (ANP, BNP and CNP), bind two classes of cell surface receptors: the guanylyl cyclase-linked A and B receptors (NPR-A and NPR-B) and the C receptor (NPR-C). The biological effects of NPs have been mainly attributed to changes in intracellular cGMP following their binding to NPR-A and NPR-B. NPR-C does not include a guanylyl cyclase domain. It has been denoted as a clearance receptor and is thought to bind and internalize NPs for ultimate degradation. However, a substantial body of biochemical work has demonstrated the ability of NPR-C to couple to inhibitory G proteins (Gi) and cause inhibition of adenylyl cyclase and activation of phospholipase-C. Recently, novel physiological effects of NPs, mediated specifically by NPR-C, have been discovered in the heart and vasculature. We have described the ability of CNP, acting via NPR-C, to selectively inhibit L-type calcium currents in atrial and ventricular myocytes, as well as in pacemaker cells (sinoatrial node myocytes). In contrast, our studies of the electrophysiological effects of CNP on cardiac fibroblasts demonstrated an NPR-C-Gi-phospholipase-C-dependent activation of a non-selective cation current mediated by transient receptor potential (TRP) channels. It is also known that CNP and BNP have important anti-proliferative effects in cardiac fibroblasts that appear to involve NPR-C. In the mammalian resistance vessels, including mesenteric and coronary arteries, CNP has been found to function as an NPR-C-dependent endothelium-derived hyperpolarizing factor that regulates local blood flow and systemic blood pressure by hyperpolarizing smooth muscle cells. In this review we highlight the role of NPR-C in mediating these NP effects in myocytes and fibroblasts from the heart as well as in vascular smooth muscle cells.
  The Journal of Physiology 02/2008; 586(2):353-66.
• Article: Human tendon behaviour and adaptation, in vivo.

  S Peter Magnusson, Marco V Narici, Constantinos N Maganaris, Michael Kjaer
  [show abstract] [hide abstract]
  ABSTRACT: Tendon properties contribute to the complex interaction of the central nervous system, muscle-tendon unit and bony structures to produce joint movement. Until recently limited information on human tendon behaviour in vivo was available; however, novel methodological advancements have enabled new insights to be gained in this area. The present review summarizes the progress made with respect to human tendon and aponeurosis function in vivo, and how tendons adapt to ageing, loading and unloading conditions. During low tensile loading or with passive lengthening not only the muscle is elongated, but also the tendon undergoes significant length changes, which may have implications for reflex responses. During active loading, the length change of the tendon far exceeds that of the aponeurosis, indicating that the aponeurosis may more effectively transfer force onto the tendon, which lengthens and stores elastic energy subsequently released during unloading, in a spring-like manner. In fact, data recently obtained in vivo confirm that, during walking, the human Achilles tendon provides elastic strain energy that can decrease the energy cost of locomotion. Also, new experimental evidence shows that, contrary to earlier beliefs, the metabolic activity in human tendon is remarkably high and this affords the tendon the ability to adapt to changing demands. With ageing and disuse there is a reduction in tendon stiffness, which can be mitigated with resistance exercises. Such adaptations seem advantageous for maintaining movement rapidity, reducing tendon stress and risk of injury, and possibly, for enabling muscles to operate closer to the optimum region of the length-tension relationship.
  The Journal of Physiology 02/2008; 586(1):71-81.
• Article: The cardiovascular challenge of exercising in the heat.

  José González-Alonso, Craig G Crandall, John M Johnson
  [show abstract] [hide abstract]
  ABSTRACT: Exercise in the heat can pose a severe challenge to human cardiovascular control, and thus the provision of oxygen to exercising muscles and vital organs, because of enhanced thermoregulatory demand for skin blood flow coupled with dehydration and hyperthermia. Cardiovascular strain, typified by reductions in cardiac output, skin and locomotor muscle blood flow and systemic and muscle oxygen delivery accompanies marked dehydration and hyperthermia during prolonged and intense exercise characteristic of many summer Olympic events. This review focuses on how the cardiovascular system is regulated when exercising in the heat and how restrictions in locomotor skeletal muscle and/or skin perfusion might limit athletic performance in hot environments.
  The Journal of Physiology 02/2008; 586(1):45-53.
• Article: Central and peripheral neuroimmune responses: hyporesponsiveness during pregnancy.

  Sarah J Spencer, Abdeslam Mouihate, Michael A Galic, Quentin J Pittman
  [show abstract] [hide abstract]
  ABSTRACT: There are periods in the life of a healthy animal (including humans) when the febrile response to an immune challenge is suppressed. One such period is during late pregnancy, particularly around the time of parturition. In the 30 or so years since this 'febrile hyporesponsiveness' was first noted, much work has been done to investigate the mechanisms and adaptive significance of this phenomenon. In this review we present some insight into how and why the body deliberately re-programmes itself to develop smaller fevers in response to an immune challenge and therefore to be potentially less successful at fighting infection.
  The Journal of Physiology 02/2008; 586(2):399-406.
• Source

  Available from: physoc.org

  Article: Erythropoietin effect on red cell and plasma volume.

  Dieter Böning
  The Journal of Physiology 02/2008; 586(1):303; author reply 305-6.
• Article: Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes.

  Philip E Chen, Matthew T Geballe, Elyse Katz, Kevin Erreger, Matthew R Livesey, Kate K O'Toole, Phuong Le, C Justin Lee, James P Snyder, Stephen F Traynelis, David J A Wyllie
  [show abstract] [hide abstract]
  ABSTRACT: Heteromeric NMDARs are composed of coagonist glycine-binding NR1 subunits and glutamate-binding NR2 subunits. The majority of functional NMDARs in the mammalian central nervous system (CNS) contain two NR1 subunits and two NR2 subunits of which there are four types (A-D). We show that the potency of a variety of endogenous and synthetic glycine-site coagonists varies between recombinant NMDARs such that the highest potency is seen at NR2D-containing and the lowest at NR2A-containing NMDARs. This heterogeneity is specified by the particular NR2 subunit within the NMDAR complex since the glycine-binding NR1 subunit is common to all NMDARs investigated. To identify the molecular determinants responsible for this heterogeneity, we generated chimeric NR2A/2D subunits where we exchanged the S1 and S2 regions that form the ligand-binding domains and coexpressed these with NR1 subunits in Xenopus laevis oocytes. Glycine concentration-response curves for NMDARs containing NR2A subunits including the NR2D S1 region gave mean glycine EC(50) values similar to NR2A(WT)-containing NMDARs. However, receptors containing NR2A subunits including the NR2D S2 region or both NR2D S1 and S2 regions gave glycine potencies similar to those seen in NR2D(WT)-containing NMDARs. In particular, two residues in the S2 region of the NR2A subunit (Lys719 and Tyr735) when mutated to the corresponding residues found in the NR2D subunit influence glycine potency. We conclude that the variation in glycine potency is caused by interactions between the NR1 and NR2 ligand-binding domains that occur following agonist binding and which may be involved in the initial conformation changes that determine channel gating.
  The Journal of Physiology 02/2008; 586(1):227-45.
• Article: Endurance exercise performance: the physiology of champions.

  Michael J Joyner, Edward F Coyle
  [show abstract] [hide abstract]
  ABSTRACT: Efforts to understand human physiology through the study of champion athletes and record performances have been ongoing for about a century. For endurance sports three main factors--maximal oxygen consumption (.VO(2,max)), the so-called 'lactate threshold' and efficiency (i.e. the oxygen cost to generate a given running speed or cycling power output)--appear to play key roles in endurance performance. and lactate threshold interact to determine the 'performance .VO(2)' which is the oxygen consumption that can be sustained for a given period of time. Efficiency interacts with the performance .VO(2) to establish the speed or power that can be generated at this oxygen consumption. This review focuses on what is currently known about how these factors interact, their utility as predictors of elite performance, and areas where there is relatively less information to guide current thinking. In this context, definitive ideas about the physiological determinants of running and cycling efficiency is relatively lacking in comparison with .VO(2,max) and the lactate threshold, and there is surprisingly limited and clear information about the genetic factors that might pre-dispose for elite performance. It should also be cautioned that complex motivational and sociological factors also play important roles in who does or does not become a champion and these factors go far beyond simple physiological explanations. Therefore, the performance of elite athletes is likely to defy the types of easy explanations sought by scientific reductionism and remain an important puzzle for those interested in physiological integration well into the future.
  The Journal of Physiology 02/2008; 586(1):35-44.
• Article: Similarity of polygenic profiles limits the potential for elite human physical performance.

  Alun G Williams, Jonathan P Folland
  [show abstract] [hide abstract]
  ABSTRACT: Human physical capability is influenced by many environmental and genetic factors, and it is generally accepted that physical capability phenotypes are highly polygenic. However, the ways in which relevant polymorphisms combine to influence the physical capability of individuals and populations are unknown. Initially, the literature was searched to identify associations between 23 genetic polymorphisms and human endurance phenotypes. Next, typical genotype frequencies of those polymorphisms in the general population were obtained from suitable literature. Using probability calculations, we found only a 0.0005% chance of a single individual in the world having the 'preferable' form of all 23 polymorphisms. As the number of DNA variants shown to be associated with human endurance phenotypes continues to increase, the probability of any single individual possessing the 'preferable' form of each polymorphism will become even lower. However, with population turnover, the chance of such genetically gifted individuals existing increases. To examine the polygenic endurance potential of a human population, a 'total genotype score' (for the 23 polymorphisms) was calculated for each individual within a hypothetical population of 1000 000. There was considerable homogeneity in terms of genetic predisposition to high endurance potential, with 99% of people differing by no more than seven genotypes from the typical profile. Consequently, with population turnover world and Olympic records should improve even without further enhancement of environmental factors, as more 'advantageous' polygenic profiles occasionally, though rarely, emerge. More broadly, human potential appears limited by the similarity of polygenic profiles at both the 'elite sport' and 'chronic disorder' ends of the performance continuum.
  The Journal of Physiology 02/2008; 586(1):113-21.