Voltage-Gated K+Currents Regulate Resting Membrane Potential and [Ca2+]iin Pulmonary Arterial Myocytes

1995 ◽  
Vol 77 (2) ◽  
pp. 370-378 ◽  
Author(s):  
Xiao-Jian Yuan
Keyword(s):  
Membrane Potential ◽  
Resting Membrane Potential ◽  
Voltage Gated ◽  
Pulmonary Arterial ◽  
K Currents

Chronic hypoxia alters effects of endothelin and angiotensin on K+ currents in pulmonary arterial myocytes

1999 ◽  
Vol 277 (3) ◽  
pp. L431-L439 ◽  
Author(s):  
Larissa A. Shimoda ◽  
J. T. Sylvester ◽  
James S. K. Sham
Keyword(s):  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Inhibitory Effect ◽  
Resting Membrane Potential ◽  
Ang Ii ◽  
Voltage Gated ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
K Currents

We tested the hypothesis that chronic hypoxia alters the regulation of K+ channels in intrapulmonary arterial smooth muscle cells (PASMCs). Charybdotoxin-insensitive, 4-aminopyridine-sensitive voltage-gated K+(KV,CI) and Ca2+-activated K+(KCa) currents were measured in freshly isolated PASMCs from rats exposed to 21 or 10% O2 for 17–21 days. In chronically hypoxic PASMCs, KV,CIcurrent was reduced and KCacurrent was enhanced. 4-Aminopyridine (10 mM) depolarized both normoxic and chronically hypoxic PASMCs, whereas charybdotoxin (100 nM) had no effect in either group. The inhibitory effect of endothelin (ET)-1 (10−7 M) on KV,CI current was significantly reduced in PASMCs from chronically hypoxic rats, whereas inhibition by angiotensin (ANG) II (10−7M) was enhanced. Neither ET-1 nor ANG II altered KCa current in normoxic PASMCs; however, both stimulated KCacurrent at positive potentials in chronically hypoxic PASMCs. These results suggest that although modulation of KV,CI and KCa channels by ET-1 and ANG II is altered by chronic hypoxia, the role of these channels in the regulation of resting membrane potential was not changed.

Hormonal Signaling Actions on Kv7.1 (KCNQ1) Channels

2021 ◽  
Vol 61 (1) ◽  
pp. 381-400
Author(s):  
Emely Thompson ◽  
Jodene Eldstrom ◽  
David Fedida
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Cardiac Action Potential ◽  
Resting Membrane Potential ◽  
Voltage Gated ◽  
M Current ◽  
Kv7 Channels ◽  
Cardiac Action ◽  
Repolarization Phase ◽  
And Control

Kv7 channels (Kv7.1–7.5) are voltage-gated K+ channels that can be modulated by five β-subunits (KCNE1–5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K+ current, IKs, which is important during the repolarization phase of the cardiac action potential. Kv7.2–7.5 are predominantly neuronally expressed and constitute the muscarinic M-current and control the resting membrane potential in neurons. Kv7.1 produces drastically different currents as a result of modulation by KCNE subunits. This flexibility allows the Kv7.1 channel to have many roles depending on location and assembly partners. The pharmacological sensitivity of Kv7.1 channels differs from that of Kv7.2–7.5 and is largely dependent upon the number of β-subunits present in the channel complex. As a result, the development of pharmaceuticals targeting Kv7.1 is problematic. This review discusses the roles and the mechanisms by which different signaling pathways affect Kv7.1 and KCNE channels and could potentially provide different ways of targeting the channel.

scholarly journals Tuning voltage-gated channel activity and cellular excitability with a sphingomyelinase

2013 ◽  
Vol 142 (4) ◽  
pp. 367-380 ◽  
Author(s):  
David J. Combs ◽  
Hyeon-Gyu Shin ◽  
Yanping Xu ◽  
Yajamana Ramu ◽  
Zhe Lu
Keyword(s):  
Membrane Potential ◽  
Mammalian Cells ◽  
Resting Membrane Potential ◽  
Xenopus Laevis Oocytes ◽  
Channel Activity ◽  
Excitable Cells ◽  
Voltage Sensors ◽  
Voltage Gated ◽  
Activated State ◽  
Gated Channel

Voltage-gated ion channels generate action potentials in excitable cells and help set the resting membrane potential in nonexcitable cells like lymphocytes. It has been difficult to investigate what kinds of phospholipids interact with these membrane proteins in their native environments and what functional impacts such interactions create. This problem might be circumvented if we could modify specific lipid types in situ. Using certain voltage-gated K+ (KV) channels heterologously expressed in Xenopus laevis oocytes as a model, our group has shown previously that sphingomyelinase (SMase) D may serve this purpose. SMase D is known to remove the choline group from sphingomyelin, a phospholipid primarily present in the outer leaflet of plasma membranes. This SMase D action lowers the energy required for voltage sensors of a KV channel to enter the activated state, causing a hyperpolarizing shift of the Q-V and G-V curves and thus activating them at more hyperpolarized potentials. Here, we find that this SMase D effect vanishes after removing most of the voltage-sensor paddle sequence, a finding supporting the notion that SMase D modification of sphingomyelin molecules alters these lipids’ interactions with voltage sensors. Then, using SMase D to probe lipid–channel interactions, we find that SMase D not only similarly stimulates voltage-gated Na+ (NaV) and Ca2+ channels but also markedly slows NaV channel inactivation. However, the latter effect is not observed in tested mammalian cells, an observation highlighting the profound impact of the membrane environment on channel function. Finally, we directly demonstrate that SMase D stimulates both native KV1.3 in nonexcitable human T lymphocytes at their typical resting membrane potential and native NaV channels in excitable cells, such that it shifts the action potential threshold in the hyperpolarized direction. These proof-of-concept studies illustrate that the voltage-gated channel activity in both excitable and nonexcitable cells can be tuned by enzymatically modifying lipid head groups.

Abstract 17301: Functional Characterization of KCNK3 Mutants Associated With Pulmonary Arterial Hypertension Under Physiologically Relevant Heterozygous Conditions

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michael S Bohnen ◽  
Danilo Roman-Campos ◽  
Cecile Terrenoire ◽  
Jack Jnani ◽  
Lei Chen ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Ph Dependence ◽  
Functional Characterization ◽  
Resting Membrane Potential ◽  
Channel Activity ◽  
Loss Of Function ◽  
Pulmonary Arterial ◽  
Specific Impact

KCNK3 encodes a two-pore domain K+ channel, TASK-1, which is inhibited by extracellular acidity and hypoxia. Expressed in a variety of tissues, including human pulmonary artery smooth muscle cells (hPASMCs), the central nervous system, pancreas, and adrenal glands, TASK-1 contributes to the resting membrane potential of cells in which it is expressed. Recently, our group reported mutations in KCNK3 underlying idiopathic pulmonary arterial hypertension (PAH), resulting from loss of TASK-1 function, partially pharmacologically rescuable with ONO-RS-082. TASK-1 dimerizes in vivo, forming functional channels with another TASK-1 subunit or with the related TASK-3 channel. TASK-1 and TASK-3 often are expressed in the same cells, although it has been reported that TASK-1 alone is expressed in the lung. Our initial study examined mutant and wildtype (WT) homodimeric TASK-1 channels expressed heterologously in COS-7 cells. Here we further characterize PAH-linked TASK-1 mutations in physiologically relevant heterozygous conditions in COS-7 and hPASMC cell lines. We engineered heterodimeric channels consisting of one mutant and one WT subunit; compared this with co-expression of mutant and WT channels; and measured channel activity with whole cell patch clamp procedures. We found a mutation specific impact of heterozygosity on channel activity. One mutation, V221L, produces a shift in pH dependence accounting for loss of function at physiological pH 7.4, partially rescued by dimerization with a WT subunit, while another, G203D, produces near complete loss of function as a homo- or hetero-dimer. The presence of TASK-3 results in greater rescue of V221L TASK-1 activity at pH 7.4 than does WT TASK-1. Additionally, under current clamp we found that ONO-RS-082 hyperpolarizes the membrane potential in hPASMCs expressing WT or V221L TASK-1, reversible by selective block of TASK-1 with ML365. Together, our results suggest (a) TASK-1 mutant heterodimers exhibit loss of function with mutation specific severity; (b) TASK-3 may rescue mutant TASK-1 and underlie a tissue specific impact of the TASK-1 mutations observed clinically; and (c) PAH TASK-1 mutants can be pharmacologically modulated in hPASMCs and alter the critically important resting membrane potential.

scholarly journals Homeostatic recovery of embryonic spinal activity initiated by compensatory changes in resting membrane potential

2019 ◽  
Author(s):  
Carlos Gonzalez-Islas ◽  
Miguel Angel Garcia-Bereguiain ◽  
Peter Wenner
Keyword(s):  
Nervous System ◽  
Membrane Potential ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Resting Membrane Potential ◽  
Receptor Blockade ◽  
Homeostatic Mechanism ◽  
Voltage Gated ◽  
Baseline Activity

AbstractWhen baseline activity in a neuronal network is modified by external challenges, a set of mechanisms is prompted to homeostatically restore activity levels. These homeostatic mechanisms are thought to be profoundly important in the maturation of the network. We have previously shown that 2-day blockade of either excitatory GABAergic or glutamatergic transmission in the living embryo transiently blocks the movements generated by spontaneous network activity (SNA) in the spinal cord. However, by 2 hours of persistent receptor blockade embryonic movements begin to recover, and by 12 hours we observe a complete homeostatic recovery in vivo. Compensatory changes in voltage-gated conductances in motoneurons were observed by 12 hours of blockade, but not changes in synaptic strength. It was unclear whether changes in voltage-gated conductances were observed by 2 hours of blockade when the recovery actually begins. Further, compensatory changes in voltage-gated conductances were not observed following glutamatergic blockade where embryonic movements were blocked but then recovered in a similar manner to GABAergic blockade. In this study, we discover a mechanism for homeostatic recovery in these first hours of neurotransmitter receptor blockade. In the first 6 hours of GABAergic or glutamatergic blockade there was a clear depolarization of resting membrane potential in both motoneurons and interneurons. These changes reduced action potential threshold and were mainly observed in the continued presence of the antagonist. Therefore, it appears that fast changes in resting membrane potential represent a key fast homeostatic mechanism for the maintenance of network activity in the living embryonic nervous system.SignificanceHomeostatic plasticity represents a set of mechanisms that act to recover cellular or network activity following a challenge to that activity and is thought to be critical for the developmental construction of the nervous system. The chick embryo afforded us the opportunity to observe in a living developing system the timing of the homeostatic recovery of network activity following 2 distinct perturbations. Because of this advantage, we have identified a novel homeostatic mechanism that actually occurs as the network recovers and is therefore likely to contribute to nervous system homeostasis. We found that a depolarization of the resting membrane potential in the first hour of the perturbations enhances excitability and supports the recovery of embryonic spinal network activity.

Serotonin depolarizes the membrane potential in rat mesenteric artery myocytes by decreasing voltage-gated K+ currents

2006 ◽  
Vol 347 (2) ◽  
pp. 468-476 ◽  
Author(s):  
Young Min Bae ◽  
Aeran Kim ◽  
Junghwan Kim ◽  
Sang Woong Park ◽  
Tae-Kyung Kim ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mesenteric Artery ◽  
Voltage Gated ◽  
Rat Mesenteric Artery ◽  
K Currents

Tamoxifen inhibits Na+ and K+ currents in rat ventricular myocytes

2003 ◽  
Vol 285 (2) ◽  
pp. H661-H668 ◽  
Author(s):  
Jianying He ◽  
Margaret E. Kargacin ◽  
Gary J. Kargacin ◽  
Christopher A. Ward
Keyword(s):  
Membrane Potential ◽  
Ventricular Myocytes ◽  
Resting Membrane Potential ◽  
Delayed Rectifier ◽  
Rat Ventricular Myocytes ◽  
Life Threatening ◽  
Prolonged Qt Interval ◽  
Electrophysiological Mechanism ◽  
K Currents ◽  
Arrhythmogenic Effects

Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. However, tamoxifen has been shown to induce QT prolongation of the electrocardiogram, thereby potentially causing life-threatening polymorphic ventricular arrhythmias. The purpose of the present study was to elucidate the electrophysiological mechanism(s) that underlie the arrhythmogenic effects of tamoxifen. We used standard ruptured whole cell and perforated patch-clamping techniques on rat ventricular myocytes to investigate the effects of tamoxifen on cardiac action potential (AP) waveforms and the underlying K+ currents. Tamoxifen (3 μmol/l) markedly prolonged AP duration, decreased maximal rate of depolarization, and decreased resting membrane potential. At this concentration, tamoxifen significantly depressed the Ca2+-independent transient outward K+ current ( Ito), sustained outward delayed rectifier K+ current ( Isus), inward rectifier K+ current ( IK1), and Na+ current ( INa) in the myocytes. Lower concentrations of tamoxifen (1 μmol/l) also decreased the resting membrane potential and significantly depressed IK1 to 79 ± 5% ( n = 5; at –120 mV) of pretreatment values. The results of this study indicate that inhibition of Ito, Isus, and IK1 by tamoxifen may underlie AP prolongation in cardiac myocytes and thereby contribute to prolonged QT interval observed in patients.

Graded response of K+ current, membrane potential, and [Ca2+]i to hypoxia in pulmonary arterial smooth muscle

2002 ◽  
Vol 283 (5) ◽  
pp. L1143-L1150 ◽  
Author(s):  
Andrea Olschewski ◽  
Zhigang Hong ◽  
Daniel P. Nelson ◽  
E. Kenneth Weir
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Cortical Neurons ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Resting Membrane Potential ◽  
Type I ◽  
Body Type ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Many studies indicate that hypoxic inhibition of some K+ channels in the membrane of the pulmonary arterial smooth muscle cells (PASMCs) plays a part in initiating hypoxic pulmonary vasoconstriction. The sensitivity of the K+ current ( I k), resting membrane potential ( E m), and intracellular Ca2+ concentration ([Ca2+]i) of PASMCs to different levels of hypoxia in these cells has not been explored fully. Reducing Po 2 levels gradually inhibited steady-state I k of rat resistance PASMCs and depolarized the cell membrane. The block of I k by hypoxia was voltage dependent in that low O2 tensions (3 and 0% O2) inhibited I k more at 0 and −20 mV than at 50 mV. As expected, the hypoxia-sensitive I k was also 4-aminopyridine sensitive. Fura 2-loaded PASMCs showed a graded increase in [Ca2+]i as Po 2 levels declined. This increase was reduced markedly by nifedipine and removal of extracellular Ca2+. We conclude that, as in the carotid body type I cells, PC-12 pheochromocytoma cells, and cortical neurons, increasing severity of hypoxia causes a proportional decrease in I k and E m and an increase of [Ca2+]i.

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