The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Alison M Gurney - One of the best experts on this subject based on the ideXlab platform.
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two pore domain k channel task 1 in pulmonary artery smooth muscle cells
Circulation Research, 2003Co-Authors: Alison M Gurney, Oleg N Osipenko, Debbi Macmillan, K M Mcfarlane, Rothwelle J Tate, Fiona E J KempsillAbstract:Pulmonary vascular tone is strongly influenced by the Resting membrane Potential of smooth muscle cells, depolarization promoting Ca2+ influx, and contraction. The Resting Potential is determined l...
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influence of chronic hypoxia on the contributions of non inactivating and delayed rectifier k currents to the Resting Potential and tone of rat pulmonary artery smooth muscle
British Journal of Pharmacology, 1998Co-Authors: O N Osipenko, D M Alexander, Margaret R Maclean, Alison M GurneyAbstract:Exposing rats to chronic hypoxia increased the 4-aminopyridine (4-AP) sensitivity of pulmonary arteries. 1 mm 4-AP caused smooth muscle cell depolarization and contraction in arteries from hypoxic rats, but had little effect in age-matched controls. Chronic hypoxia downregulated delayed rectifier K+ current (IK(V)), which was nearly 50% blocked by 1 mm 4-AP, and non-inactivating K+ current (IK(N)), which was little affected by 1 mm 4-AP. The results suggest that IK(N) determines Resting Potential in control rats and that its downregulation following hypoxia leads to depolarization, which activates IK(V) and increases its contribution to Resting Potential. The hypoxia-induced increase in 4-AP sensitivity thus reflects a switch in the major K+ current determining Resting Potential, from IK(N) to IK(V). This has important implications for the actions and specificity of pulmonary vasodilator drugs. British Journal of Pharmacology (1998) 124, 1335–1337; doi:10.1038/sj.bjp.0702006
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regulation of the Resting Potential of rabbit pulmonary artery myocytes by a low threshold o2 sensing potassium current
British Journal of Pharmacology, 1997Co-Authors: Oleg N Osipenko, Mark A Evans, Alison M GurneyAbstract:The contributions of specific K+ currents to the Resting membrane Potential of rabbit isolated, pulmonary artery myocytes, and their modulation by hypoxia, were investigated by use of the whole-cell, patch-clamp technique. In the presence of 10 μm glibenclamide the Resting Potential (−50±4 mV, n=18) was unaffected by 10 μm tetraethylammonium ions, 200 nm charybdotoxin, 200 nm iberiotoxin, 100 μm ouabain or 100 μm digitoxin. The negative Potential was therefore maintained without ATP-sensitive (KATP) or large conductance Ca2+-sensitive (BKCa) K channels, and without the Na+-K+ATPase. The Resting Potential, the delayed rectifier current (IK(V)) and the A-like K+ current (IK(A)) were all reduced in a concentration-dependent manner by 4-aminopyridine (4-AP) and by quinine. 4-AP was equally potent at reducing the Resting Potential and IK(V), 10 mm causing depolarization from −44 mV to −22 mV with accompanying inhibition of IK(V) by 56% and IK(A) by 79%. In marked contrast, the effects of quinine on Resting Potential were poorly correlated with its effects on both IK(A) and IK(V). At 10 mm, quinine reduced IK(V) and IK(A) by 47% and 38%, respectively, with no change in the Resting Potential. At 100 μm, both currents were almost abolished while the Resting Potential was reduced <50%. Raising the concentration to 1 mm had little further effect on IK(A) or IK(V), but essentially abolished the Resting Potential. Reduction of the Resting Potential by quinine was correlated with inhibition of a voltage-gated, low threshold, non-inactivating K+ current, IK(N). Thus, 100 μm quinine reduced both IK(N) and the Resting Potential by around 50%. The Resting membrane Potential was the same whether measured after clamping the cell at −80 mV, or immediately after a prolonged period of depolarization at 0 mV, which inactivated IK(A) and IK(V), but not IK(N). When exposed to a hypoxic solution, the O2 tension near the cell fell from 125±6 to 14±2 mmHg (n=20), resulting in a slow depolarization of the myocyte membrane to −35±3 mV (n=16). The depolarization occurred without a change in the amplitude of IK(V) or IK(A), but it was accompanied by 60% inhibition of IK(N) at 0 mV. Our findings suggest that the Resting Potential of rabbit pulmonary artery myocytes depends on IK(N), and that inhibition of IK(N) may mediate the depolarization induced by hypoxia. British Journal of Pharmacology (1997) 120, 1461–1470; doi:10.1038/sj.bjp.0701075
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properties of a novel k current that is active at Resting Potential in rabbit pulmonary artery smooth muscle cells
The Journal of Physiology, 1996Co-Authors: A M Evans, O N Osipenko, Alison M GurneyAbstract:1. An outward current (IK(N)) was identified in rabbit pulmonary artery myocytes, which persisted after Ca(2+)-activated and ATP-sensitive K+ currents were blocked by TEA (10 mM) and glibenclamide (10 microM), respectively, and after A-like (IK(A)) and delayed rectifer (IK(V)) K+ currents were inactivated by clamping the cell at 0 mV for 10 min. It was found in smooth muscle cells at all levels of the pulmonary arterial tree. 2. The relationship between the reversal Potential of IK(N) and the extracellular K+ concentration ([K+]o) was close to that expected for a K(+)-selective channel. Deviation from Nernstian behaviour at low [K+)o could be accounted for by the presence of an accompanying leakage current. 3. IK(N) is voltage gated. It has a low threshold for activation, between -80 and -65 mV, and activates slowly without delay. Activation follows an exponential time course with a time constant of 1.6 s at -60 mV. Deactivation is an order of magnitude faster than activation, with a time constant of 107 ms at -60 mV. 4. IK(N) showed a similar sensitivity to 4-aminopyridine as IK(A) and IK(V), with 49% inhibition at 10 mM. The current was not blocked by microM quinine, which did inhibit IK(A) and IK(V), by 51 and 47%, respectively. 5. Activation of IK(N) was detected at Potentials close to the Resting membrane Potential of pulmonary artery smooth muscle cells, under physiological conditions. Thus it is likely to contribute to the Resting membrane Potential of these cells.
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atp sensitive k channels regulate Resting Potential of pulmonary arterial smooth muscle cells
American Journal of Physiology-heart and Circulatory Physiology, 1992Co-Authors: Lucie H Clapp, Alison M GurneyAbstract:ATP-sensitive K+ (KATP) channels have been proposed to be the target for hyperpolarizing vasodilators. However, the existence of a whole cell KATP current that can regulate membrane Potential has not been demonstrated in vascular muscle. Using the patch-clamp technique, we have examined the effects of varying intracellular ATP on membrane Potential and currents in isolated rabbit pulmonary arterial smooth muscle cells. With 1 mM ATP in the pipette, cells had a mean Resting Potential of -55 mV. When ATP was omitted, the Resting Potential became significantly more hyperpolarized (-70 mV) and the depolarizing response to the KATP-channel blocker, glibenclamide, was potentiated. In contrast, the hyperpolarizing effect of lemakalim was reduced. These hyperpolarized Resting Potentials were associated with increased activity of a basal, glibenclamide-sensitive time-independent K+ current. Furthermore, flash photolysis of ATP, 3-O-[1(4,5-dimethoxy-2-nitrophenyl)ethyl] ester, disodium salt ("caged ATP") in ATP-depleted cells caused rapid depolarization (less than 1 s) and block of the background K+ current. Our results are consistent with the idea that intracellular ATP can directly modulate the Resting Potential by inhibition of K+ channels. We propose that this ATP-sensitive K+ current plays an important role in the maintenance of the Resting Potential in arterial muscle.
Laurence O Trussell - One of the best experts on this subject based on the ideXlab platform.
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kcnq5 channels control Resting properties and release probability of a synapse
Nature Neuroscience, 2011Co-Authors: Hai Huang, Laurence O TrussellAbstract:Little is known about which ion channels determine the Resting electrical properties of presynaptic membranes. In recordings made from the rat calyx of Held, a giant mammalian terminal, we found Resting Potential to be controlled by KCNQ (Kv7) K(+) channels, most probably KCNQ5 (Kv7.5) homomers. Unlike most KCNQ channels, which are activated only by depolarizing stimuli, the presynaptic channels began to activate just below the Resting Potential. As a result, blockers and activators of KCNQ5 depolarized or hyperpolarized nerve terminals, respectively, markedly altering Resting conductance. Moreover, the background conductance set by KCNQ5 channels, together with Na(+) and hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, determined the size and time course of the response to subthreshold stimuli. Signaling pathways known to directly affect exocytic machinery also regulated KCNQ5 channels, and increase or decrease of KCNQ5 channel activity controlled release probability through alterations in Resting Potential. Thus, ion channel determinants of presynaptic Resting Potential also control synaptic strength.
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KCNQ5 channels control Resting properties and release probability of a synapse
Nature neuroscience, 2011Co-Authors: Hai Huang, Laurence O TrussellAbstract:Huang and Trussell show that Resting Potential of the calyx of Held synapse is controlled by KCNQ5 potassium channels. Unlike most KCNQ channels, which activate only on depolarization, these presynaptic channels activate negative to the Resting Potential. These channels set the Resting conductance and control release probability of the synapse.
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modulation of transmitter release by presynaptic Resting Potential and background calcium levels
Neuron, 2005Co-Authors: Gautam B Awatramani, Gareth D Price, Laurence O TrussellAbstract:Summary Activation of presynaptic ion channels alters the membrane Potential of nerve terminals, leading to changes in transmitter release. To study the relationship between Resting Potential and exocytosis, we combined pre- and postsynaptic electrophysiological recordings with presynaptic Ca 2+ measurements at the calyx of Held. Depolarization of the membrane Potential to between −60 mV and −65 mV elicited P/Q-type Ca 2+ currents of 2+ by 2+ elevations were sufficient to enhance the probability of transmitter release up to 2-fold, with no effect on the readily releasable pool of vesicles. Moreover, the effects of mild depolarization on release had slow kinetics and were abolished by 1 mM intraterminal EGTA, suggesting that Ca 2+ acted through a high-affinity binding site. Together, these studies suggest that control of Resting Potential is a powerful means for regulating synaptic function at mammalian synapses.
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modulation of transmitter release by presynaptic Resting Potential and background calcium levels
Neuron, 2005Co-Authors: Gautam B Awatramani, Gareth D Price, Laurence O TrussellAbstract:Activation of presynaptic ion channels alters the membrane Potential of nerve terminals, leading to changes in transmitter release. To study the relationship between Resting Potential and exocytosis, we combined pre- and postsynaptic electrophysiological recordings with presynaptic Ca(2+) measurements at the calyx of Held. Depolarization of the membrane Potential to between -60 mV and -65 mV elicited P/Q-type Ca(2+) currents of < 1 pA and increased intraterminal Ca(2+) by < 100 nM. These small Ca(2+) elevations were sufficient to enhance the probability of transmitter release up to 2-fold, with no effect on the readily releasable pool of vesicles. Moreover, the effects of mild depolarization on release had slow kinetics and were abolished by 1 mM intraterminal EGTA, suggesting that Ca(2+) acted through a high-affinity binding site. Together, these studies suggest that control of Resting Potential is a powerful means for regulating synaptic function at mammalian synapses.
Hai Huang - One of the best experts on this subject based on the ideXlab platform.
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kcnq5 channels control Resting properties and release probability of a synapse
Nature Neuroscience, 2011Co-Authors: Hai Huang, Laurence O TrussellAbstract:Little is known about which ion channels determine the Resting electrical properties of presynaptic membranes. In recordings made from the rat calyx of Held, a giant mammalian terminal, we found Resting Potential to be controlled by KCNQ (Kv7) K(+) channels, most probably KCNQ5 (Kv7.5) homomers. Unlike most KCNQ channels, which are activated only by depolarizing stimuli, the presynaptic channels began to activate just below the Resting Potential. As a result, blockers and activators of KCNQ5 depolarized or hyperpolarized nerve terminals, respectively, markedly altering Resting conductance. Moreover, the background conductance set by KCNQ5 channels, together with Na(+) and hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, determined the size and time course of the response to subthreshold stimuli. Signaling pathways known to directly affect exocytic machinery also regulated KCNQ5 channels, and increase or decrease of KCNQ5 channel activity controlled release probability through alterations in Resting Potential. Thus, ion channel determinants of presynaptic Resting Potential also control synaptic strength.
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KCNQ5 channels control Resting properties and release probability of a synapse
Nature neuroscience, 2011Co-Authors: Hai Huang, Laurence O TrussellAbstract:Huang and Trussell show that Resting Potential of the calyx of Held synapse is controlled by KCNQ5 potassium channels. Unlike most KCNQ channels, which activate only on depolarization, these presynaptic channels activate negative to the Resting Potential. These channels set the Resting conductance and control release probability of the synapse.
Wayne R Giles - One of the best experts on this subject based on the ideXlab platform.
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the Resting Potential and k currents in primary human articular chondrocytes
Frontiers in Physiology, 2018Co-Authors: Mary M Maleckar, R B Clark, Bartholomew J Votta, Wayne R GilesAbstract:Human transplant programs provide significant opportunities for detailed in vitro assessments of physiological properties of selected tissues and cell types. We present a semi-quantitative study of the fundamental electrophysiological/biophysical characteristics of human chondrocytes, focused on K+ transport mechanisms, and their ability to regulate to the Resting membrane Potential, Em. Patch clamp studies on these enzymatically isolated human chondrocytes reveal consistent expression of at least three functionally distinct K+ currents, as well as transient receptor Potential (TRP) currents. The small size of these cells and their exceptionally low current densities present significant technical challenges for electrophysiological recordings. These limitations have been addressed by parallel development of a mathematical model of these K+ and TRP channel ion transfer mechanisms in an attempt to reveal their contributions to Em. In combination, these experimental results and simulations yield new insights into: (i) the ionic basis for Em and its expected range of values; (ii) modulation of Em by the unique articular joint extracellular milieu; (iii) some aspects of TRP channel mediated depolarization-secretion coupling; (iv) some of the essential biophysical principles that regulate K+ channel function in "chondrons." The chondron denotes the chondrocyte and its immediate extracellular compartment. The presence of discrete localized surface charges and associated zeta Potentials at the chondrocyte surface are regulated by cell metabolism and can modulate interactions of chondrocytes with the extracellular matrix. Semi-quantitative analysis of these factors in chondrocyte/chondron function may yield insights into progressive osteoarthritis.
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rigorous phenotyping of cardiac ipsc preparations requires knowledge of their Resting Potential s
Biophysical Journal, 2016Co-Authors: Wayne R Giles, Denis NobleAbstract:In a recent “Biophysical Letter” (1), voltage-sensitive dye methods were used to record action Potentials from populations of human-induced pluripotent stem-cell-derived cardiac myocytes (iPSC-CMs) that had been maintained in defined cell culture conditions. The main goal of this study was to determine whether chamber-specific (i.e., atrial versus ventricular) action Potential waveforms (2) could be identified consistently from these cardiocytes. The data shows that the action Potential waveforms depend strongly on cell culture density.
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a mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts
Biophysical Journal, 2007Co-Authors: Andrew K Maccannell, R B Clark, Hojjat Bazzazi, Lisa Chilton, Yoshiyuki Shibukawa, Wayne R GilesAbstract:Functional intercellular coupling has been demonstrated among networks of cardiac fibroblasts, as well as between fibroblasts and atrial or ventricular myocytes. In this study, the consequences of these interactions were examined by implementing the ten Tusscher model of the human ventricular action Potential, and coupling it to our electrophysiological models for mammalian ventricular fibroblasts. Our simulations reveal significant electrophysiological consequences of coupling between 1 and 4 fibroblasts to a single ventricular myocyte. These include alterations in plateau height and/or action Potential duration (APD) and changes in underlying ionic currents. Two series of simulations were carried out. First, fibroblasts were modeled as a spherical cell with a capacitance of 6.3 pF and an ohmic membrane resistance of 10.7 GΩ. When these “passive” fibroblasts were coupled to a myocyte, they caused slight prolongation of APD with no changes in the plateau, threshold for firing, or rate of initial depolarization. In contrast, when the same myocyte-fibroblast complexes were modeled after addition of the time- and voltage-gated K+ currents that are expressed in fibroblasts, much more pronounced effects were observed: the plateau height of the action Potential was reduced and the APD shortened significantly. In addition, each fibroblast exhibited significant electrotonic depolarizations in response to each myocyte action Potential and the Resting Potential of the fibroblasts closely approximated the Resting Potential of the coupled ventricular myocyte.
O N Osipenko - One of the best experts on this subject based on the ideXlab platform.
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influence of chronic hypoxia on the contributions of non inactivating and delayed rectifier k currents to the Resting Potential and tone of rat pulmonary artery smooth muscle
British Journal of Pharmacology, 1998Co-Authors: O N Osipenko, D M Alexander, Margaret R Maclean, Alison M GurneyAbstract:Exposing rats to chronic hypoxia increased the 4-aminopyridine (4-AP) sensitivity of pulmonary arteries. 1 mm 4-AP caused smooth muscle cell depolarization and contraction in arteries from hypoxic rats, but had little effect in age-matched controls. Chronic hypoxia downregulated delayed rectifier K+ current (IK(V)), which was nearly 50% blocked by 1 mm 4-AP, and non-inactivating K+ current (IK(N)), which was little affected by 1 mm 4-AP. The results suggest that IK(N) determines Resting Potential in control rats and that its downregulation following hypoxia leads to depolarization, which activates IK(V) and increases its contribution to Resting Potential. The hypoxia-induced increase in 4-AP sensitivity thus reflects a switch in the major K+ current determining Resting Potential, from IK(N) to IK(V). This has important implications for the actions and specificity of pulmonary vasodilator drugs. British Journal of Pharmacology (1998) 124, 1335–1337; doi:10.1038/sj.bjp.0702006
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properties of a novel k current that is active at Resting Potential in rabbit pulmonary artery smooth muscle cells
The Journal of Physiology, 1996Co-Authors: A M Evans, O N Osipenko, Alison M GurneyAbstract:1. An outward current (IK(N)) was identified in rabbit pulmonary artery myocytes, which persisted after Ca(2+)-activated and ATP-sensitive K+ currents were blocked by TEA (10 mM) and glibenclamide (10 microM), respectively, and after A-like (IK(A)) and delayed rectifer (IK(V)) K+ currents were inactivated by clamping the cell at 0 mV for 10 min. It was found in smooth muscle cells at all levels of the pulmonary arterial tree. 2. The relationship between the reversal Potential of IK(N) and the extracellular K+ concentration ([K+]o) was close to that expected for a K(+)-selective channel. Deviation from Nernstian behaviour at low [K+)o could be accounted for by the presence of an accompanying leakage current. 3. IK(N) is voltage gated. It has a low threshold for activation, between -80 and -65 mV, and activates slowly without delay. Activation follows an exponential time course with a time constant of 1.6 s at -60 mV. Deactivation is an order of magnitude faster than activation, with a time constant of 107 ms at -60 mV. 4. IK(N) showed a similar sensitivity to 4-aminopyridine as IK(A) and IK(V), with 49% inhibition at 10 mM. The current was not blocked by microM quinine, which did inhibit IK(A) and IK(V), by 51 and 47%, respectively. 5. Activation of IK(N) was detected at Potentials close to the Resting membrane Potential of pulmonary artery smooth muscle cells, under physiological conditions. Thus it is likely to contribute to the Resting membrane Potential of these cells.
