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Activation Threshold (activation + threshold)

Distribution by Scientific Domains

Medical Sciences	54%

Selected Abstracts

Peripheral sensitization in migraine,role for P2X purinergic receptors in the dura,vascular sensory pathway

DRUG DEVELOPMENT RESEARCH, Issue 6 2007
Ernest A. Jennings
Abstract Peripheral sensitization is still considered a prime contributor underlying the mechanisms of migraine. Trigeminal primary afferent neurons are the first neurons in the dural nociceptive pathway, and activation results in conscious perception of pain. Peripheral sensitization can lower the activation threshold of primary afferent neurons, rendering them more excitable, allowing for increases in release of neurotransmitter from both central and peripheral terminals. Increase in neurotransmitter release from central terminals contributes to excitation of second-order neurons, while the release of peptides from peripheral terminals has been implicated in neurogenic inflammation. Adenosine 5,-triphosphate (ATP) causes pain in human studies, and depolarize sensory neurons. There is evidence of the action of ATP at many levels in the dura,vascular sensory pathway. Animal studies have shown that some P2X receptors are located in neurons innervating the dura, including the P2X3 receptor, which is most often shown to be involved in nociceptive pathways. In this article, we briefly review peripheral sensitization in relation to migraine and provide emphasis for P2X receptor involvement where it is available. Drug Dev Res 68:321,328, 2007. © 2007 Wiley-Liss, Inc. [source]

TLR2 engagement on CD8 T cells lowers the thresholdfor optimal antigen-induced T cell activation

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2006
Anne Cottalorda
Abstract TLR have a crucial role in the detection of microbial infection in mammals. Until recently, most investigations on TLR have focused on cells of the innate immune system and on the role of TLR in the initiation of antigen-specific responses following recognition of microbial products by APC. Here, we report that murine T cells express TLR1, TLR2, TLR6, TLR7 and TLR9 mRNA. Using CD8 T cells from F5 TCR-transgenic mice, we demonstrate that the lipopeptide Pam3CysSK4 (Pam), a synthetic analog of bacterial and mycoplasmal lipoproteins that recognizes TLR1/2 complex, costimulates antigen-activated T cells. Costimulation with Pam permits an increased cell proliferation and survival associated with a sustained CD25 expression and an enhanced expression of Bcl-xL anti-apoptotic protein. In addition, we show that costimulation with Pam up-regulates IFN-, production but also granzyme,B secretion and cytotoxic activity of antigen-activated T cells, indicating that TLR2 engagement enhances the major effector functions of CD8 T cells. Finally, we demonstrate that TLR2 engagement on T cells lowers the activation threshold for costimulatory signals delivered by APC. [source]

Weak agonist self-peptides promote selection and tuning of virus-specific T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2003
Samuel
Abstract Recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. To identify and further examine self-peptides that can mediate positive selection, we searched a protein-database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined P14 transgenic TCR. We identified four peptides that could bind the restriction element H-2Db and induce proliferation of P14 transgenic splenocytes at high concentration. Two of the four peptides (DBM and RPP) were able to positively select thevirus-specific TCR in fetal thymic organ culture but were unable to induce clonal deletion. Reverse-phase HPLC and mass spectrometry demonstrated that these peptides were presented by H-2Db molecules on thymic epithelial cell lines. We also examined whether the selecting ligands altered T cell responsiveness in vitro. DBM-selected T cells lost their ability to respond to the positively selecting ligand DBM, whereas RPP-selected T cells only retainrd their ability to respond to high concentrations of RPP. These results demonstrate that self-peptides that mediate positiveselection can differentially "tune" the activation threshold of T cells and alter the functional repertoire of T cells. [source]

Heterogeneity of Ventricular Fibrillation Dominant Frequency During Global Ischemia in Isolated Rabbit Hearts

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2007
Ch.B. , JANE CALDWELL M.B.
Introduction: Ventricular fibrillation (VF) studies show that ECG-dominant frequency (DF) decreases as ischemia develops. This study investigates the contribution of the principle ischemic metabolic components to this decline. Methods and Results: Rabbit hearts were Langendorff-perfused at 40 mL/min with Tyrode's solution and loaded with RH237. Epicardial optical action potentials were recorded with a photodiode array (256 sites, 15 × 15 mm). After 60 seconds of VF (induced by burst pacing), global ischemia was produced by low flow (6 mL/min), or the solution changed to impose hypoxia (95% N2/5% CO2), low pHo (6.7, 80% O2/20% CO2), or raised [K+]o (8 mM). DF of the optical signals was determined at each site. Conduction velocity (CV), action potential duration (APD90), effective refractory period (ERP), activation threshold, dV/dtmax, and membrane potential were measured in separate experiments during ventricular pacing. During VF, ischemia decreased DF in the left ventricle (LV) (to [58 ± 6]%, P < 0.001), but not the right (RV) ([93 ± 5]%). Raised [K+]o reproduced this DF pattern (LV: [67 ± 12]%, P < 0.001; RV: [95 ± 9]%). LV DF remained elevated in hypoxia or low pHo. During ventricular pacing, ischemia decreased CV in LV but not RV. Raised [K+]o did not change CV in either ventricle. Ischemia and raised [K+]o shortened APD90 without altering ERP. LV activation threshold increased in both ischemia and raised [K+]o and was associated with diastolic depolarization and decreased dV/dtmax. Conclusions: These results suggest that during VF, decreased ECG DF in global ischemia is largely due to elevated [K+]o affecting the activation thresholds in the LV rather than RV. [source]

A mini linac based positron source

PHYSICA STATUS SOLIDI (C) - CURRENT TOPICS IN SOLID STATE PHYSICS, Issue 11 2009
Patrice Pérez
Abstract We have installed in Saclay a demonstration setup for an intense positron source in November 2008. It is based on a compact 6 MeV electron linac to produce positrons via pair production on a tungsten target. A relatively high current of 0.15 mA compensates the low energy, which is below the neutron activation threshold. The expected production rate is 4x1011 fast positrons per second. A set of coils is arranged to select the fast positrons from the diffracted electron beam in order to study the possibility to use a rare gas cryogenic moderator away from the main flux of particles. A first part of the commissioning of the linac has been performed. First attempts at measuring the fast positron flux are underway. This setup is part of a project to demonstrate the feasibility of an experiment to produce the H+ ion for a free fall measurement of neutral antihydrogen (H). Its small size and cost could be of interest for a university laboratory or industry for materials science applications. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source]

The evolutionarily conserved residue A653 plays a key role in HERG channel closing

THE JOURNAL OF PHYSIOLOGY, Issue 11 2009
Svetlana Z. Stepanovic
Human ether-a-go-go- related gene (HERG) encodes the rapid, outwardly rectifying K+ current IKr that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or unintended pharmaceutical block of IKr can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653) that is highly conserved among evolutionarily divergent K+ channels. HERG-A653 is close to the ,glycine hinge' implicated in K+ channel opening, and is flanked by tyrosine 652 and phenylalanine 656, which contribute to the drug binding site. We substituted an array of seven (I, C, S, G, Y, V and T) amino acids at position 653 and expressed individual variants in heterologous systems to assess changes in gating and drug binding. Substitution of A653 resulted in negative shifts of the V1/2 of activation ranging from ,23.6 (A653S) to ,62.5 (A653V) compared to ,11.2 mV for wild-type (WT). Deactivation was also drastically altered: channels with A653I/C substitutions exhibited delayed deactivation in response to test potentials above the activation threshold, while A653S/G/Y/V/T failed to deactivate under those conditions and required hyperpolarization and prolonged holding potentials at ,130 mV. While A653S/G/T/Y variants showed decreased sensitivity to the IKr inhibitor dofetilide, these changes could not be correlated with defects in channel closure. Homology modelling suggests that in the closed state, A653 forms tight contacts with several residues from the neighbouring subunit in the tetramer, playing a key role in S6 helix packing at the narrowest part of the vestibule. Our study suggests that A653 plays an important functional role in the outwardly rectifying gating behaviour of HERG, supporting channel closure at membrane potentials negative to the channel activation threshold. [source]

Functional expression of the hyperpolarization-activated, non-selective cation current If in immortalized HL-1 cardiomyocytes

THE JOURNAL OF PHYSIOLOGY, Issue 1 2002
Laura Sartiani
HL-1 cells are adult mouse atrial myocytes induced to proliferate indefinitely by SV40 large T antigen. These cells beat spontaneously when confluent and express several adult cardiac cell markers including the outward delayed rectifier K+ channel. Here, we examined the presence of a hyperpolarization-activated If current in HL-1 cells using the whole-cell patch-clamp technique on isolated cells enzymatically dissociated from the culture at confluence. Cell membrane capacitance (Cm) ranged from 5 to 53 pF. If was detected in about 30 % of the cells and its occurrence was independent of the stage of the culture. If maximal slope conductance was 89.7 ± 0.4 pS pF,1 (n= 10). If current in HL-1 cells showed typical characteristics of native cardiac If current: activation threshold between ,50 and ,60 mV, half-maximal activation potential of ,83.1 ± 0.7 mV (n= 50), reversal potential at ,20.8 ± 1.5 mV (n= 10), time-dependent activation by hyperpolarization and blockade by 4 mm Cs+. In half of the cells tested, activation of adenylyl cyclase by the forskolin analogue L858051 (20 ,m) induced both a ,6 mV positive shift of the half-activation potential and a ,37 % increase in the fully activated If current. RT-PCR analysis of the hyperpolarization-activated, cyclic nucleotide-gated channels (HCN) expressed in HL-1 cells demonstrated major contributions of HCN1 and HCN2 channel isoforms to If current. Cytosolic Ca2+ oscillations in spontaneously beating HL-1 cells were measured in Fluo-3 AM-loaded cells using a fast-scanning confocal microscope. The oscillation frequency ranged from 1.3 to 5 Hz and the spontaneous activity was stopped in the presence of 4 mm Cs+. Action potentials from HL-1 cells had a triangular shape, with an overshoot at +15 mV and a maximal diastolic potential of ,69 mV, i.e. more negative than the threshold potential for If activation. In conclusion, HL-1 cells display a hyperpolarization-activated If current which might contribute to the spontaneous contractile activity of these cells. [source]

Voltage-activated proton currents in human lymphocytes

THE JOURNAL OF PHYSIOLOGY, Issue 1 2002
Tom Schilling
Voltage-activated proton currents are reported for the first time in human peripheral blood T and B lymphocytes and in the human leukaemic T cell line Jurkat E6-1. The properties of H+ currents studied using tight-seal voltage-clamp recording techniques were similar in all cells. Changing the pH gradient by one unit caused a 47 mV shift in the reversal potential, demonstrating high selectivity of the channels for protons. H+ current activation upon membrane depolarisation had a sigmoidal time course that could be fitted by a single exponential function after a brief delay. Increasing pHo shifted the activation threshold to more negative potentials, and increased both the H+ current amplitude and the rate of activation. In lymphocytes studied at pHi 6.0, the activation threshold was more negative and the H+ current density was three times larger than at pHi 7.0. Increasing the intracellular Ca2+ concentration to 1 ,m did not change H+ current amplitude or kinetics detectably. Extracellularly applied Zn2+ and Cd2+ inhibited proton currents, slowing activation and shifting the voltage-activation curve to more positive potentials. The H+ current amplitude was 100 times larger in CD19+ B lymphocytes and in Jurkat E6-1 cells than in CD3+ T lymphocytes. Following stimulation with the phorbol ester PMA, the H+ current density in peripheral blood T lymphocytes and Jurkat T cells increased. In contrast, the H+ current density of phorbol ester (PMA)-stimulated B lymphocytes was reduced and activation became slower. The pattern of expression of H+ channels in lymphocytes appears well suited to their proposed role of charge compensation during the respiratory burst. [source]