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Journal of Physiology

Jeng-Haur Chen, Weiyi Xu, David N Sheppard
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated Cl(-) channel defective in the genetic disease cystic fibrosis (CF). The gating behaviour of CFTR is characterized by bursts of channel openings interrupted by brief, flickery closures, separated by long closures between bursts. Entry to and exit from an open burst is controlled by the interaction of ATP with two ATP-binding sites, sites 1 and 2 in CFTR. To understand better the kinetic basis of CFTR intraburst gating, we investigated the single-channel activity of human CFTR at different intracellular pH (pHi ) values...
October 25, 2016: Journal of Physiology
Iva Bruhova, Anthony Auerbach
Acetylcholine (ACh) released at the vertebrate nerve-muscle synapse is hydrolyzed rapidly into choline (Cho), so endplate receptors (AChRs) are exposed to high concentrations of both of these structurally-related ligands. To understand how these receptors distinguish ACh and Cho, we used single-channel electrophysiology to measure resting affinities (binding free energies) of these and other agonists in adult-type mouse AChRs having a mutation(s) at the transmitter-binding sites. The aromatic rings of αY190, αW149 and αY198 each provide ∼50% less binding energy for Cho compared to ACh...
October 25, 2016: Journal of Physiology
François Seghers, Xavier Yerna, Nadège Zanou, Olivier Devuyst, Rudi Vennekens, Bernd Nilius, Philippe Gailly
The renin - angiotensin system is a crucial blood pressure regulation system. It consists of a hormonal cascade where the rate-limiting enzyme is renin, which is secreted in blood flow by renal juxtaglomerular (JG) cells in response to low pressure in the renal afferent arteriole. In contrast, an increase in blood pressure results in a decreased renin secretion. This is accompanied by a transitory increase in [Ca(2+) ]i of JG cells. The inverse relationship between [Ca(2+) ]i and renin secretion has been called the "calcium paradox" of renin release...
October 25, 2016: Journal of Physiology
Zheng Zhang, Hannah A Ledford, Seojin Park, Wenying Wang, Sassan Rafizadeh, Hyo Jeong Kim, Wilson Xu, Ling Lu, Victor C Lau, Anne A Knowlton, Xiao-Dong Zhang, Ebenezer N Yamoah, Nipavan Chiamvimonvat
The normal function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane. Small-conductance, Ca(2+) -activated K(+) channels (SK, KCa 2) are expressed in human atrial myocytes and responsible for shaping atrial action potentials. Understanding the mechanisms of SK channel trafficking may provide new insights into the regulation controlling the repolarization of atrial myocytes. We have previously demonstrated that the C and N termini of SK2 channels interact with actin-binding proteins, α-actinin2 and filamin A, respectively...
October 25, 2016: Journal of Physiology
Alex I Wiesman, Elizabeth Heinrichs-Graham, Nathan M Coolidge, James E Gehringer, Max J Kurz, Tony W Wilson
Sensory gating (SG) is a phenomenon in which neuronal responses to subsequent similar stimuli are weaker, and is thought to be an important mechanism for preventing excessive environmental stimulation from overloading shared neural resources. Although gating has been demonstrated in multiple sensory systems, the neural dynamics and developmental trajectory underlying SG remain poorly understood. Herein, we adopt a data-driven approach to map the spectro-temporal amplitude and functional connectivity (FC) dynamics that support gating in the somatosensory system (somato-SG) in healthy children and adolescents using magnetoencephalography (MEG)...
October 25, 2016: Journal of Physiology
Ryan A Devenyi, Francis A Ortega, Willemijn Groenendaal, Trine Krogh-Madsen, David J Christini, Eric A Sobie
Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. Here we combined mathematical modeling with information-rich dynamic-clamp experiments to elucidate regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell...
October 24, 2016: Journal of Physiology
Naoto Fujii, Brendan D McNeely, Glen P Kenny
β-adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, however, the mechanisms underpinning this response remains unresolved. We evaluated the hypotheses that 1) nitric oxide synthase (NOS) contributes to β-adrenergic cutaneous vasodilatation, whereas cyclooxygenase (COX) limits the vasodilatation, and 2) COX contributes to β-adrenergic sweating. In 10 young males (25 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites infused with 1) lactated Ringer's (control), 2) 10 mm L -NNA, a non-specific NOS inhibitor, 3) 10 mM ketorolac, a non-specific COX inhibitor, or 4) a combination of L -NNA and ketorolac...
October 24, 2016: Journal of Physiology
J Pingel, E M Bartels, J B Nielsen
Muscle contractures are common in patients with central motor lesions, but the mechanisms responsible for the development of contractures are still unclear. Increased or decreased neural activation, protracted placement of a joint with the muscle in a short position and muscle atrophy have been suggested to be involved, but none of these mechanisms are sufficient to explain the development of muscle contractures alone. Here we propose that changes in tissue homeostasis in the neuro-muscular-tendon-connective tissue complex is at the heart of the development of contractures, and that an integrated physiological understanding of the interaction between neural, mechanical and metabolic factors, as well as genetic and epigenetic factors, is necessary in order to unravel the mechanisms that result in muscle contractures...
October 24, 2016: Journal of Physiology
Lorenza Brocca, Luana Toniolo, Carlo Reggiani, Roberto Bottinelli, Marco Sandri, Maria Antonietta Pellegrino
Muscle atrophy is a complex process that is in common with many different catabolic diseases including disuse/inactivity and ageing. The signalling pathways that control the atrophy program in the different disuse/inactivity conditions have not yet been completely dissected. It has been recently reported that inhibition of FoxO only partially spared muscle mass after denervation. The purposes of this study were: (i) to determine the involvement of FoxOs in hindlimb suspension disuse model, (ii) to define whether the molecular events of protein breakdown are shared among different unloaded muscles and finally (iii) to compare the data obtained in this model with another model of inactivity such as denervation...
October 21, 2016: Journal of Physiology
Derek Garden, Arianna Rinaldi, Matthew F Nolan
The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs...
October 21, 2016: Journal of Physiology
Luca Fusi, Valentina Percario, Elisabetta Brunello, Marco Caremani, Pasquale Bianco, Joseph D Powers, Massimo Reconditi, Vincenzo Lombardi, Gabriella Piazzesi
KEY POINTS: Myosin filament mechanosensing determines the efficiency of the contraction by adapting the number of switched ON motors to the load. Accordingly, the unloaded shortening velocity (V0 ) is already set at the end of the latency relaxation (LR), ∼10 ms after the start of stimulation, when the myosin filament is still in the OFF state. Here the number of actin-attached motors per half-myosin filament (n) during V0 shortening imposed either at the end of LR or at the plateau of the isometric contraction is estimated from the relation between half-sarcomere compliance and force during the force redevelopment after the shortening...
October 20, 2016: Journal of Physiology
Sher Ali, Tao Xu, Xiaolan Xu
Ca(2+) release-activated Ca(2+) (CRAC) channels play an essential role in the immune system. The pore-forming subunit, Orai1, is an important pharmacological target. Here, we summarize the recent discoveries on the structure-function relationship of Orai1, as well as its interaction with the native channel opener STIM1 and chemical modulator 2-aminoethoxydiphenyl borate (2-APB). We first introduce the critical structural elements of Orai1, which include a Ca(2+) accumulating region (CAR), ion selectivity filter, hydrophobic centre, basic region, extended transmembrane orai1 N-terminal (ETON), transmembrane (TM) regions 2 and 3, P245 bend, (263) SHK(265) hinge linker and L273-L276 hydrophobic patch...
October 18, 2016: Journal of Physiology
Jian Shi, Francesc Miralles, Lutz Birnbaumer, William A Large, Anthony P Albert
In vascular smooth muscle cells (VSMCs), stimulation of TRPC1-based SOCs mediate Ca(2+) entry pathways which regulate contractility, proliferation and migration. It is therefore important to understand how these channels are activated. Studies have shown that stimulation of TRPC1-based SOCs requires Gαq/PLCβ1 activities and PKC phosphorylation, but it is unclear how store depletion stimulates this gating pathway. The present work examines this issue by focusing on the role of STIM1, an endo/sarcoplasmic reticulum Ca(2+) sensor...
October 18, 2016: Journal of Physiology
Reza Farivar, Simon Clavagnier, Bruce C Hansen, Ben Thompson, Robert F Hess
Complex natural scenes can be decomposed into their oriented spatial frequency (SF) and phase relationships, both of which are represented locally at the earliest stages of cortical visual processing. The SF preference map in the human cortex, obtained using synthetic stimuli, is orderly and correlates strongly with eccentricity. In addition, early visual areas show sensitivity to the phase information that describes the relationship between SFs and thereby dictates the structure of the image. Taken together, two possibilities arise for the joint representation of SF and phase: either the entirety of the cortical SF map is uniformly sensitive to phase, or a particular set of SFs is selectively phase sensitive-for example, greater phase sensitivity for higher SFs that define fine-scale edges in a complex scene...
October 17, 2016: Journal of Physiology
Martin J MacInnis, Martin J Gibala
Interval exercise typically involves repeated bouts of relatively intense exercise interspersed by short periods of recovery. A common classification scheme subdivides this method into high-intensity interval training (HIIT; 'near maximal' efforts) and sprint interval training (SIT; 'supramaximal' efforts). Both forms of interval training induce the classic physiological adaptations characteristic of moderate-intensity continuous training (MICT) such as increased aerobic capacity (VO2max ) and mitochondrial content...
October 17, 2016: Journal of Physiology
Emilio A Herrera, Francisca Cifuentes-Zúñiga, Esteban Figueroa, Cristian Villanueva, Cherie Hernández, René Alegría, Viviana Arroyo, Estefania Peñaloza, Marcelo Farías, Ricardo Uauy, Paola Casanello, Bernardo J Krause
In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetyl cysteine (NAC) on fetal endothelial function and eNOS programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, receiving half of the sows NAC in the drinking water (from day 34 until term)...
October 14, 2016: Journal of Physiology
Tianzheng Yu, Patricia Deuster, Yifan Chen
The regulation of mitochondrial morphology is closely coupled to cell survival during stress. We examined changes in the mitochondrial morphology of mouse C2C12 skeletal muscle cells in response to heat acclimation and heat shock exposure. Acclimated cells showed a greater survival rate during heat shock exposure than non-acclimated cells, and were characterized by long interconnected mitochondria and reduced expression of dynamin-related protein 1 (Drp1) for their mitochondrial fractions. Exposure of C2C12 muscle cells to heat shock led to apoptotic death featuring activation of caspase 3/7, release of cytochrome c and loss of cell membrane integrity...
October 12, 2016: Journal of Physiology
Craig P Smith, Raymond F Reynolds
When using our arms to interact with the world, unintended body motion can introduce movement error. A mechanism which could detect and compensate for such motion would be beneficial. Observations of arm movements evoked by vestibular stimulation provide some support for this mechanism. However, the physiological function underlying these artificially-evoked movements is unclear from previous research. For such a mechanism to be functional, it should only operate when the arm is being controlled in an earth-fixed rather than body-fixed reference frame...
October 12, 2016: Journal of Physiology
C Wilson, M Lee, J G McCarron
Circulating blood generates frictional forces (shear-stress) on the walls of blood vessels. These frictional forces critically regulate vascular function. The endothelium senses these frictional forces and, in response, releases various vasodilators that relax smooth muscle cells in a process termed flow-mediated dilatation. Whilst some elements of the signalling mechanisms have been identified, precisely how flow is sensed and transduced to cause the release of relaxing factors is poorly understood. By imaging signalling in large areas of the endothelium of intact arteries, we show that the endothelium responds to flow by releasing acetylcholine...
October 12, 2016: Journal of Physiology
Olusoji A T Afuwape, Catherine R Wasser, Thomas Schikorski, Ege T Kavalali
Earlier studies suggest that spontaneous and evoked neurotransmitter release processes are maintained by synaptic vesicles which are segregated into functionally distinct pools. However, direct interrogation of the link between this putative synaptic vesicle pool heterogeneity and neurotransmission has been difficult. To examine this link, we tagged vesicles with horseradish peroxidase (HRP) - a heme containing plant enzyme - or antibodies against synaptotagmin-1 (syt1). Filling recycling vesicles in hippocampal neurons with HRP and subsequent treatment with hydrogen peroxide (H2 O2 ) modified the properties of neurotransmitter release depending on the route of HRP uptake...
October 10, 2016: Journal of Physiology
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