scholarly journals Second-Generation Histamine H1 Receptor Antagonists Suppress Delayed Rectifier K+-Channel Currents in Murine Thymocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Kazutomo Saito ◽  
Nozomu Abe ◽  
Hiroaki Toyama ◽  
Yutaka Ejima ◽  
Masanori Yamauchi ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Second Generation ◽  
Membrane Capacitance ◽  
K Channel ◽  
Delayed Rectifier ◽  
Cell Recording ◽  
Voltage Dependent ◽  
Proliferation Of Lymphocytes ◽  
First Time ◽  
Channel Currents

Background/Aims. Voltage-dependent potassium channels (Kv1.3) are predominantly expressed in lymphocyte plasma membranes. These channels are critical for the activation and proliferation of lymphocytes. Since second-generation antihistamines are lipophilic and exert immunomodulatory effects, they are thought to affect the lymphocyte Kv1.3-channel currents. Methods. Using the patch-clamp whole-cell recording technique in murine thymocytes, we tested the effects of second-generation antihistamines, such as cetirizine, fexofenadine, azelastine, and terfenadine, on the channel currents and the membrane capacitance. Results. These drugs suppressed the peak and the pulse-end currents of the channels, although the effects of azelastine and terfenadine on the peak currents were more marked than those of cetirizine and fexofenadine. Both azelastine and terfenadine significantly lowered the membrane capacitance. Since these drugs did not affect the process of endocytosis in lymphocytes, they were thought to have interacted directly with the plasma membranes. Conclusions. Our study revealed for the first time that second-generation antihistamines, including cetirizine, fexofenadine, azelastine, and terfenadine, exert suppressive effects on lymphocyte Kv1.3-channels. The efficacy of these drugs may be related to their immunomodulatory mechanisms that reduce the synthesis of inflammatory cytokine.

Differential Oxidative Modulation of Voltage-Dependent K+ Currents in Rat Hippocampal Neurons

2002 ◽  
Vol 87 (6) ◽  
pp. 2990-2995 ◽  
Author(s):  
Wolfgang Müller ◽  
Katrin Bittner
Keyword(s):  
Hydrogen Peroxide ◽  
Hippocampal Neurons ◽  
Immune Defense ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Cell Recording ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
K Currents ◽  
Stimulation Of

Oxidative stress is enhanced by [Ca2+]i-dependent stimulation of phospholipases and mitochondria and has been implicated in immune defense, ischemia, and excitotoxicity. Using whole cell recording from hippocampal neurons, we show that arachidonic acid (AA) and hydrogen peroxide (H2O2) both reduce the transient K+ current I A by −54 and −68%, respectively, and shift steady-state inactivation by −10 and −15 mV, respectively. While AA was effective at an extracellular concentration of 1 μM and an intracellular concentration of 1 pM, extracellular H2O2 was equally effective only at a concentration >800 μM (0.0027%). In contrast to AA, H2O2 decreased the slope of activation and increased the slope of inactivation of I A and reduced the sustained delayed rectifier current I K(V) by 22% and shifted its activation by −9 mV. Intracellular application of the antioxidant glutathione (GSH, 2–5 mM) blocked all effects of AA and the reduction of I A by H2O2. In contrast, intracellular GSH enhanced reduction of I K(V) by H2O2. Decrease of the slope of activation and increase of the slope of inactivation of I A by hydrogen peroxide was blocked and reversed to a decrease, respectively, by intracellular application of GSH. Intracellular GSH did not prevent H2O2 to shift inactivation and activation of I A and activation of I K(V) to more negative potentials. We conclude, that AA and H2O2modulate voltage-activated K currents differentially by oxidation of GSH accessible intracellular and GSH inaccessible extracellular K+-channel domains, thereby presumably affecting neuronal information processing and oxidative damage.

Dynamic regulation of the voltage-gated Kv2.1 potassium channel by multisite phosphorylation

2007 ◽  
Vol 35 (5) ◽  
pp. 1064-1068 ◽  
Author(s):  
D.P. Mohapatra ◽  
K.-S. Park ◽  
J.S. Trimmer
Keyword(s):  
Neuronal Excitability ◽  
Critical Role ◽  
Functional Characterization ◽  
K Channel ◽  
Delayed Rectifier ◽  
Dynamic Regulation ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Specific Regulation

Voltage-gated K+ channels are key regulators of neuronal excitability. The Kv2.1 voltage-gated K+ channel is the major delayed rectifier K+ channel expressed in most central neurons, where it exists as a highly phosphorylated protein. Kv2.1 plays a critical role in homoeostatic regulation of intrinsic neuronal excitability through its activity- and calcineurin-dependent dephosphorylation. Here, we review studies leading to the identification and functional characterization of in vivo Kv2.1 phosphorylation sites, a subset of which contribute to graded modulation of voltage-dependent gating. These findings show that distinct developmental-, cell- and state-specific regulation of phosphorylation at specific sites confers a diversity of functions on Kv2.1 that is critical to its role as a regulator of intrinsic neuronal excitability.

Ba2+, TEA+, and quinine effects on apical membrane K+ conductance and maxi K+ channels in gallbladder epithelium

1990 ◽  
Vol 259 (1) ◽  
pp. C56-C68 ◽  
Author(s):  
Y. Segal ◽  
L. Reuss
Keyword(s):  
Apical Membrane ◽  
Membrane Conductance ◽  
Membrane Resistance ◽  
K Channel ◽  
Dependent Manner ◽  
Gallbladder Epithelium ◽  
Concentration Dependent Manner ◽  
K Channels ◽  
Voltage Dependent ◽  
Channel Currents

The apical membrane of Necturus gallbladder epithelium contains a voltage-activated K+ conductance [Ga(V)]. Large-conductance (maxi) K+ channels underlie Ga(V) and account for 17% of the membrane conductance (Ga) under control conditions. We examined the Ba2+, tetraethylammonium (TEA+), and quinine sensitivities of Ga and single maxi K+ channels. Mucosal Ba2+ addition decreased resting Ga in a concentration-dependent manner (65% block at 5 mM) and decreased Ga(V) in a concentration- and voltage-dependent manner. Mucosal TEA+ addition also decreased control Ga (60% reduction at 5 mM). TEA+ block of Ga(V) was more potent and less voltage dependent that Ba2+ block. Maxi K+ channels were blocked by external Ba2+ at millimolar levels and by external TEA+ at submillimolar levels. At 0.3 mM, quinine (mucosal addition) hyperpolarized the cell membranes by 6 mV and reduced the fractional apical membrane resistance by 50%, suggesting activation of an apical membrane K+ conductance. At 1 mM, quinine both activated and blocked K(+)-conductive pathways. Quinine blocked maxi K+ channel currents at submillimolar concentrations. We conclude that 1) Ba2+ and TEA+ block maxi K+ channels and other K+ channels underlying resting Ga; 2) parallels between the Ba2+ and TEA+ sensitivities of Ga(V) and maxi K+ channels support a role for these channels in Ga(V); and 3) quinine has multiple effects on K(+)-conductive pathways in gallbladder epithelium, which are only partially explained by block of apical membrane maxi K+ channels.

Complexity of the outward K+ current of the rat megakaryocyte

1997 ◽  
Vol 272 (5) ◽  
pp. C1525-C1531 ◽  
Author(s):  
E. Romero ◽  
R. Sullivan
Keyword(s):  
K Channel ◽  
Delayed Rectifier ◽  
Channel Blockers ◽  
Excitable Cells ◽  
Electrophysiological Properties ◽  
Relative Contribution ◽  
Delayed Rectifier Current ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
K Current

Megakaryocytes isolated from rat bone marrow express a voltage-dependent, outward K+ current with complex kinetics of activation and inactivation. We found that this current could be separated into at least two components based on differential responses to K+ channel blockers. One component, which exhibited features of the "transient" or "A-type" K+ current of excitable cells, was more strongly blocked by 4-aminopyridine (4-AP) than by tetrabutylammonium (TBA). This current, which we designated as "4-AP-sensitive" current, activated rapidly at potentials more positive than -40 mV and subsequently underwent rapid voltage-dependent inactivation. A separate current that activated slowly was blocked much more effectively by TBA than by 4-AP. This "TBA-sensitive" component, which resembled a typical delayed rectifier current, was much more resistant to voltage-dependent inactivation. The relative contribution of each of these components varied from cell to cell. The effect of charybdotoxin was similar to that of 4-AP. Our data indicate that the voltage-dependent K+ current of resting megakaryocytes is more complex than heretofore believed and support the emerging concept that megakaryocytes possess intricate electrophysiological properties.

Testosterone-induced relaxation of rat aorta is androgen structure specific and involves K+ channel activation

2001 ◽  
Vol 91 (6) ◽  
pp. 2742-2750 ◽  
Author(s):  
Andrew Q. Ding ◽  
John N. Stallone
Keyword(s):  
Rank Order ◽  
Specific Effect ◽  
Rat Aorta ◽  
Isometric Tension ◽  
K Channel ◽  
Delayed Rectifier ◽  
Sprague Dawley ◽  
Voltage Dependent ◽  
Rat Thoracic Aorta ◽  
Lower Permeability

Recent studies have established that testosterone (Tes) produces acute (nongenomic) vasorelaxation. This study examined the structural specificity of Tes-induced vasorelaxation and the role of vascular smooth muscle (VSM) K+ channels in rat thoracic aorta. Aortic rings from male Sprague-Dawley rats with (Endo+) and without endothelium (Endo−) were prepared for isometric tension recording. In Endo− aortas precontracted with phenylephrine, 5–300 μM Tes produced dose-dependent relaxation from 10 μM (4 ± 1%) to 300 μM (100 ± 1%). In paired Endo+ and Endo− aortas, Tes-induced vasorelaxation was slightly but significantly greater in Endo+ aortas (at 5–150 μM Tes); sensitivity (EC50) of the aorta to Tes was reduced by nearly one-half in Endo− vessels. Based on the sensitivity (EC50) of Endo− aortas, Tes, the active metabolite 5α-dihydrotestosterone, the major excretory metabolites androsterone and etiocholanolone, the nonpolar esters Tes-enanthate and Tes-hemisuccinate (THS), and THS conjugates to BSA (THS-BSA) exhibited relative potencies for vasorelaxation dramatically different from androgen receptor-mediated effects observed in reproductive tissues, with a rank order of THS-BSA > Tes > androsterone = THS = etiocholanolone > dihydrotestosterone ≫ Tes-enanthate. Pretreatment of aortas with 5 mM 4-aminopyridine attenuated Tes-induced vasorelaxation by an average of 44 ± 2% (25–300 μM Tes). In contrast, pretreatment of aortas with other K+ channel inhibitors had no effect. These data reveal that Tes-induced vasorelaxation is a structurally specific effect of the androgen molecule, which is enhanced in more polar analogs that have a lower permeability to the VSM cell membrane, and that the effect of Tes involves activation of K+ efflux through K+channels in VSM, perhaps via the voltage-dependent (delayed-rectifier) K+ channel.

scholarly journals Permeation of Na+ through a delayed rectifier K+ channel in chick dorsal root ganglion neurons.

1994 ◽  
Vol 104 (4) ◽  
pp. 747-771 ◽  
Author(s):  
M J Callahan ◽  
S J Korn
Keyword(s):  
Dorsal Root Ganglion ◽  
Binding Site ◽  
Dorsal Root ◽  
Reversal Potential ◽  
Dorsal Root Ganglion Neurons ◽  
K Channel ◽  
Delayed Rectifier ◽  
Cation Binding Site ◽  
Voltage Dependent ◽  
Ganglion Neurons

In whole-cell patch clamp recordings from chick dorsal root ganglion neurons, removal of intracellular K+ resulted in the appearance of a large, voltage-dependent inward tail current (Icat). Icat was not Ca2+ dependent and was not blocked by Cd2+, but was blocked by Ba2+. The reversal potential for Icat shifted with the Nernst potential for [Na+]. The channel responsible for Icat had a cation permeability sequence of Na+ > Li+ > TMA+ > NMG+ (PX/PNa = 1:0.33:0.1:0) and was impermeable to Cl-. Addition of high intracellular concentrations of K+, Cs+, or Rb+ prevented the occurrence of Icat. Inhibition of Icat by intracellular K+ was voltage dependent, with an IC50 that ranged from 3.0-8.9 mM at membrane potentials between -50 and -110 mV. This voltage-dependent shift in IC50 (e-fold per 52 mV) is consistent with a single cation binding site approximately 50% of the distance into the membrane field. Icat displayed anomolous mole fraction behavior with respect to Na+ and K+; Icat was inhibited by 5 mM extracellular K+ in the presence of 160 mM Na+ and potentiated by equimolar substitution of 80 mM K+ for Na+. The percent inhibition produced by both extracellular and intracellular K+ at 5 mM was identical. Reversal potential measurements revealed that K+ was 65-105 times more permeant than Na+ through the Icat channel. Icat exhibited the same voltage and time dependence of inactivation, the same voltage dependence of activation, and the same macroscopic conductance as the delayed rectifier K+ current in these neurons. We conclude that Icat is a Na+ current that passes through a delayed rectifier K+ channel when intracellular K+ is reduced to below 30 mM. At intracellular K+ concentrations between 1 and 30 mM, PK/PNa remained constant while the conductance at -50 mV varied from 80 to 0% of maximum. These data suggest that the high selectivity of these channels for K+ over Na+ is due to the inability of Na+ to compete with K+ for an intracellular binding site, rather than a barrier that excludes Na+ from entry into the channel or a barrier such as a selectivity filter that prevents Na+ ions from passing through the channel.

ATP-sensitive K + -channel run-down is Mg 2+ dependent

1990 ◽  
Vol 240 (1298) ◽  
pp. 397-410 ◽  
Keyword(s):  
State Probability ◽  
K Channel ◽  
Channel Activity ◽  
Channel Current ◽  
Phosphatase Inhibitor ◽  
Voltage Dependent ◽  
Insulin Secreting Cells ◽  
Channel Currents

ATP-sensitive K + -channel currents were recorded from isolated mem­brane patches and voltage-clamped CRI-G1 insulin-secreting cells. Inter­nal Mg 2+ ions inhibited ATP-K + channels by a voltage-dependent block of the channel current and decrease of open-state probability. The run­ down of ATP-K + channel activity was also shown to be [Mg 2+ ] i depen­dent, being almost abolished in Mg 2+ -free conditions. Substitution of Mn 2+ for Mg 2+ did not prevent run-down, nor did the presence of phos­phate-donating nucleotides, a protease or phosphatase inhibitor or replacement of Cl by gluconate.

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