scholarly journals Idiosyncratic Gating of HERG-like K+ Channels in Microglia

1998 ◽  
Vol 111 (6) ◽  
pp. 795-805 ◽  
Author(s):  
Peter S. Pennefather ◽  
Wei Zhou ◽  
Thomas E. DeCoursey
Keyword(s):  
Slow Component ◽  
Outward Current ◽  
Data Availability ◽  
Transient Outward Current ◽  
Maximal Conductance ◽  
Voltage Dependent ◽  
Simple Kinetic Model ◽  
Window Current ◽  
Herg Channels ◽  
Deactivation Process

A simple kinetic model is presented to explain the gating of a HERG-like voltage-gated K+ conductance described in the accompanying paper (Zhou, W., F.S. Cayabyab, P.S. Pennefather, L.C. Schlichter, and T.E. DeCoursey. 1998. J. Gen. Physiol. 111:781–794). The model proposes two kinetically distinct closing pathways, a rapid one favored by depolarization (deactivation) and a slow one favored by hyperpolarization (inactivation). The overlap of these two processes leads to a window current between −50 and +20 mV with a peak at −36 mV of ∼12% maximal conductance. The near absence of depolarization-activated outward current in microglia, compared with HERG channels expressed in oocytes or cardiac myocytes, can be explained if activation is shifted negatively in microglia. As seen with experimental data, availability predicted by the model was more steeply voltage dependent, and the midpoint more positive when determined by making the holding potential progressively more positive at intervals of 20 s (starting at −120 mV), rather than progressively more negative (starting at 40 mV). In the model, this hysteresis was generated by postulating slow and ultra-slow components of inactivation. The ultra-slow component takes minutes to equilibrate at −40 mV but is steeply voltage dependent, leading to protocol-dependent modulation of the HERG-like current. The data suggest that “deactivation” and “inactivation” are coupled through the open state. This is particularly evident in isotonic Cs+, where a delayed and transient outward current develops on depolarization with a decay time constant more voltage dependent and slower than the deactivation process observed at the same potential after a brief hyperpolarization.

Identification of and developmental changes in transient outward current in embryonic chick cardiomyocytes

1995 ◽  
Vol 7 (5) ◽  
pp. 1369 ◽  
Author(s):  
H Satoh
Keyword(s):  
Slow Component ◽  
Outward Current ◽  
Cell Voltage ◽  
Developmental Changes ◽  
Transient Outward Current ◽  
Embryonic Chick ◽  
Time To Peak ◽  
Ventricular Cells ◽  
Developmental Age ◽  
Voltage Dependent

Identification and developmental changes in the transient outward current (I(to)) in isolated embryonic chick ventricular cells (3, 10 and 17 days old) were examined using a whole-cell voltage clamp technique. Experiments were performed at room temperature (22 degrees C). Test pulses were applied between -40 and +50 mV from a holding potential of -60 mV. The I(to) was present (but small) and increased during development; the current density of I(to) at +40 mV was 3.5 +/- 0.5 pA/pF (n = 7) in 3-day cells, 4.2 +/- 0.9 pA/pF (n = 5) in 10-day cells, and 17.1 +/- 1.6 pA/pF (n = 5) in 17-day-old cells. The average capacitances also changed with developmental age; 12.0 +/- 2.0 pF (n = 8) in 3-day cells, 10.8 +/- 2.2 pF (n = 7) in 10-day cells, and 8.6 +/- 2.3 pF (n = 7) in 17-day cells. The I(to) was not always observed in all the prepared cells, and the number of cells possessing I(to) increased during development. The threshold potential was -30 mV in 17-day cells, and appeared to be displaced to more negative potential with developmental age. The time to peak decreased during development: 10.6 +/- 1.1 ms (n = 4) in 3-day cells, 6.7 +/- 0.5 ms (n = 5) in 10-day cells, and 5.4 +/- 0.6 ms (n = 5) in 17-day cells. The time decay of the inactivation phase for the I(to) had two exponentials; the fast component was increased by about 3-fold in 17-day cells, and the slow component was decreased by about 14% in both 10- and 17-day cells, as compared to 3-day cells. Addition of 3 mM 4-aminopyridine (4-AP) inhibited I(to) at +50 mV by 81.9 +/- 2.3% (n = 4, P < 0.001). These results indicate that the I(to), voltage-dependent and 4-AP-sensitive, exists even in young embryonic cardiomyocytes (but not in all cells), and increases during development, resulting in modulation of the action potential configuration.

Activators of protein kinase C decrease Ca2+ spark frequency in smooth muscle cells from cerebral arteries

1997 ◽  
Vol 273 (6) ◽  
pp. C2090-C2095 ◽  
Author(s):  
Adrian D. Bonev ◽  
Jonathan H. Jaggar ◽  
Michael Rubart ◽  
Mark T. Nelson
Keyword(s):  
Protein Kinase C ◽  
Membrane Potential ◽  
Protein Kinase ◽  
Cerebral Arteries ◽  
Outward Current ◽  
Transient Outward Current ◽  
Open Probability ◽  
Kinase C ◽  
Voltage Dependent ◽  
Channel Currents

Local Ca2+ transients (“Ca2+ sparks”) caused by the opening of one or the coordinated opening of a number of tightly clustered ryanodine-sensitive Ca2+-release (RyR) channels in the sarcoplasmic reticulum (SR) activate nearby Ca2+-dependent K+(KCa) channels to cause an outward current [referred to as a “spontaneous transient outward current” (STOC)]. These KCa currents cause membrane potential hyperpolarization of arterial myocytes, which would lead to vasodilation through decreasing Ca2+ entry through voltage-dependent Ca2+ channels. Therefore, modulation of Ca2+spark frequency should be a means to regulation of KCa channel currents and hence membrane potential. We examined the frequency modulation of Ca2+ sparks and STOCs by activation of protein kinase C (PKC). The PKC activators, phorbol 12-myristate 13-acetate (PMA; 10 nM) and 1,2-dioctanoyl- sn-glycerol (1 μM), decreased Ca2+ spark frequency by 72% and 60%, respectively, and PMA reduced STOC frequency by 83%. PMA also decreased STOC amplitude by 22%, which could be explained by an observed reduction (29%) in KCa channel open probability in the absence of Ca2+ sparks. The reduction in STOC frequency occurred in the presence of an inorganic blocker (Cd2+) of voltage-dependent Ca2+ channels. The reduction in Ca2+ spark frequency did not result from SR Ca2+ depletion, since caffeine-induced Ca2+ transients did not decrease in the presence of PMA. These results suggest that activators of PKC can modulate the frequency of Ca2+ sparks, through an effect on the RyR channel, which would decrease STOC frequency (i.e., KCa channel activity).

scholarly journals Whole-cell clamp of dissociated photoreceptors from the eye of Lima scabra.

1991 ◽  
Vol 97 (1) ◽  
pp. 35-54 ◽  
Author(s):  
E Nasi
Keyword(s):  
Calcium Influx ◽  
Large Fraction ◽  
Outward Current ◽  
Light Response ◽  
Stimulus Onset ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Whole Cell ◽  
Inward Current ◽  
Voltage Dependent

Voltage-dependent membrane currents were investigated in enzymatically dissociated photoreceptors of Lima scabra using the whole-cell clamp technique. Depolarizing steps to voltages more positive than -10 mV elicit a transient inward current followed by a delayed, sustained outward current. The outward current is insensitive to replacement of a large fraction of extracellular Cl- with the impermeant anion glucuronate. Superfusion with tetraethylammonium and 4-aminopyridine reversibly abolishes the outward current, and internal perfusion with cesium also suppresses it, indicating that it is mediated by potassium channels. Isolation of the inward current reveals a fast activation kinetics, the peak amplitude occurring as early as 4-5 ms after stimulus onset, and a relatively rapid, though incomplete inactivation. Within the range of voltages examined, spanning up to +90 mV, reversal was not observed. The inward current is not sensitive to tetrodotoxin at concentrations up to 10 microM, and survives replacement of extracellular Na with tetramethylammonium. On the other hand, it is completely eliminated by calcium removal from the perfusing solution, and it is partially blocked by submillimolar concentrations of cadmium, suggesting that it is entirely due to voltage-dependent calcium channels. Analysis of the kinetics and voltage dependence of the isolated calcium current indicates the presence of two components, possibly reflecting the existence of separate populations of channels. Barium and strontium can pass through these channels, though less easily than calcium. Both the activation and the inactivation become significantly more sluggish when these ions serve as the charge carrier. A large fraction of the outward current is activated by preceding calcium influx. Suppression of this calcium-dependent potassium current shows a small residual component resembling the delayed rectifier. In addition, a transient outward current sensitive to 4-aminopyridine (Ia) could also be identified. The relevance of such conductance mechanisms in the generation of the light response in Lima photoreceptors is discussed.

Characterization of a transient outward K+ current with inward rectification in canine ventricular myocytes

1998 ◽  
Vol 274 (3) ◽  
pp. C577-C585 ◽  
Author(s):  
Gui-Rong Li ◽  
Haiying Sun ◽  
Stanley Nattel
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Outward Current ◽  
Equilibrium Potential ◽  
Inward Rectification ◽  
Transient Outward Current ◽  
Membrane Excitability ◽  
Voltage Dependent ◽  
Patch Technique

The threshold potential for the classical depolarization-activated transient outward K+ current and Cl− current is positive to −30 mV. With the whole cell patch technique, a transient outward current was elicited in the presence of 5 mM 4-aminopyridine (4-AP) and 5 μM ryanodine at voltages positive to the K+ equilibrium potential in canine ventricular myocytes. The current was abolished by 200 μM Ba2+ or omission of external K+([Formula: see text]) and showed biexponential inactivation. The current-voltage relation for the peak of the transient outward component showed moderate inward rectification. The transient outward current demonstrated voltage-dependent inactivation (half-inactivation voltage: −43.5 ± 3.2 mV) and rapid, monoexponential recovery from inactivation (time constant: 13.2 ± 2.5 ms). The reversal potential responded to the changes in[Formula: see text] concentration. Action potential clamp revealed two phases of Ba2+-sensitive current during the action potential, including a large early transient component after the upstroke and a later outward component during phase 3 repolarization. The present study demonstrates that depolarization may elicit a Ba2+- and[Formula: see text]-sensitive, 4-AP-insensitive, transient outward current with inward rectification in canine ventricular myocytes. The properties of this K+ current suggest that it may carry a significant early outward current upon depolarization that may play a role in determining membrane excitability and action potential morphology.

A maturational shift in pulmonary K+ channels, from Ca2+ sensitive to voltage dependent

1998 ◽  
Vol 275 (6) ◽  
pp. L1019-L1025 ◽  
Author(s):  
Helen L. Reeve ◽  
E. Kenneth Weir ◽  
Stephen L. Archer ◽  
David N. Cornfield
Keyword(s):  
Pulmonary Circulation ◽  
Acute Hypoxia ◽  
Outward Current ◽  
Resting Membrane Potential ◽  
Transient Outward Current ◽  
Abrupt Decrease ◽  
Whole Cell ◽  
Electrophysiological Properties ◽  
Voltage Dependent ◽  
Intracellular Ca

The mechanism responsible for the abrupt decrease in resistance of the pulmonary circulation at birth may include changes in the activity of O2-sensitive K+ channels. We characterized the electrophysiological properties of fetal and adult ovine pulmonary arterial (PA) smooth muscle cells (SMCs) using conventional and amphotericin B-perforated patch-clamp techniques. Whole cell K+ currents of fetal PASMCs in hypoxia were small and characteristic of spontaneously transient outward currents. The average resting membrane potential (RMP) was −36 ± 3 mV and could be depolarized by charybdotoxin (100 nM) or tetraethylammonium chloride (5 mM; both blockers of Ca2+-dependent K+ channels) but not by 4-aminopyridine (4-AP; 1 mM; blocker of voltage-gated K+ channels) or glibenclamide (10 μM; blocker of ATP-dependent K+channels). In hypoxia, chelation of intracellular Ca2+ by 5 mM 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid further reduced the amplitude of the whole cell K+ current and prevented spontaneously transient outward current activity. Under these conditions, the remaining current was partially inhibited by 1 mM 4-AP. K+ currents of fetal PASMCs maintained in normoxia were not significantly reduced by acute hypoxia. In normoxic adult PASMCs, whole cell K+ currents were large and RMP was −49 ± 3 mV. These 4-AP-sensitive K+ currents were partially inhibited by exposure to acute hypoxia. We conclude that the K+ channel regulating RMP in the ovine pulmonary circulation changes after birth from a Ca2+-dependent K+ channel to a voltage-dependent K+ channel. The maturational-dependent differences in the mechanism of the response to acute hypoxia may be due to this difference in K+ channels.

Electrotonic load triggers remodeling of repolarizing current Ito in ventricle

2004 ◽  
Vol 286 (5) ◽  
pp. H1901-H1909 ◽  
Author(s):  
Imad Libbus ◽  
Xiaoping Wan ◽  
David S. Rosenbaum
Keyword(s):  
Phase 1 ◽  
Outward Current ◽  
Ventricular Myocardium ◽  
Underlying Mechanism ◽  
Transient Outward Current ◽  
Short Time Scale ◽  
Epicardial Cells ◽  
Voltage Dependent ◽  
Epicardial Pacing ◽  
Activation Sequence

A change in activation sequence electrically remodels ventricular myocardium, causing persistent changes in repolarizing currents (T-wave memory). However, the underlying mechanism for triggering activation sequence-dependent remodeling is unknown. Optical action potentials were mapped with high resolution from the epicardial surface of the arterially perfused canine wedge preparation ( n = 23) during 30 min of baseline endocardial stimulation, followed by 40 min of epicardial stimulation, and, finally, restoration of endocardial stimulation. Immediately after the change from endocardial to epicardial stimulation, phase 1 notch amplitude of epicardial cells was attenuated by 74 ± 8% ( P < 0.001) compared with baseline and continued to diminish during the period of epicardial pacing, suggesting progressive remodeling of the transient outward current ( Ito). When endocardial pacing was restored, notch amplitude did not immediately recover but remained attenuated by 23 ± 10% ( P < 0.001), also consistent with a remodeling effect. Peak Ito current measured from isolated epicardial myocytes changed by 12 ± 4% ( P < 0.025), providing direct evidence for Ito remodeling occurring on a surprisingly short time scale. The mechanism for triggering remodeling of Ito was a significant reduction (by 14 ± 4%, P < 0.001) of upstroke amplitude in epicardial cells during epicardial stimulation. Reduction in upstroke amplitude during epicardial pacing was explained by electrotonic load on epicardial cells by fully repolarized downstream endocardial cells. These data suggest a novel mechanism for triggering electrical remodeling in the ventricle. Electrotonic load imposed by a change in activation sequence reduces upstroke amplitude, which, in turn, attenuates Ito according to its known voltage-dependent properties, triggering downregulation of current.

scholarly journals Structure and Function of Kv4-Family Transient Potassium Channels

2004 ◽  
Vol 84 (3) ◽  
pp. 803-833 ◽  
Author(s):  
Shari G. Birnbaum ◽  
Andrew W. Varga ◽  
Li-Lian Yuan ◽  
Anne E. Anderson ◽  
J. David Sweatt ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Outward Current ◽  
Membrane Properties ◽  
Transient Outward Current ◽  
Kinetic Properties ◽  
Membrane Excitability ◽  
Channel Trafficking ◽  
System A ◽  
Voltage Dependent ◽  
And Function

Shal-type (Kv4.x) K+ channels are expressed in a variety of tissue, with particularly high levels in the brain and heart. These channels are the primary subunits that contribute to transient, voltage-dependent K+ currents in the nervous system (A currents) and the heart (transient outward current). Recent studies have revealed an enormous degree of complexity in the regulation of these channels. In this review, we describe the surprisingly large number of ancillary subunits and scaffolding proteins that can interact with the primary subunits, resulting in alterations in channel trafficking and kinetic properties. Furthermore, we discuss posttranslational modification of Kv4.x channel function with an emphasis on the role of kinase modulation of these channels in regulating membrane properties. This concept is especially intriguing as Kv4.2 channels may integrate a variety of intracellular signaling cascades into a coordinated output that dynamically modulates membrane excitability. Finally, the pathophysiology that may arise from dysregulation of these channels is also reviewed.

Calcium and potassium currents in the fast coxal depressor motor neuron of the cockroach Periplaneta americana

1995 ◽  
Vol 74 (5) ◽  
pp. 2043-2050 ◽  
Author(s):  
J. A. David ◽  
R. M. Pitman
Keyword(s):  
Motor Neuron ◽  
Periplaneta Americana ◽  
Outward Current ◽  
Potassium Currents ◽  
Transient Outward Current ◽  
Potential Range ◽  
Inward Current ◽  
Outward Currents ◽  
Current Voltage ◽  
Voltage Dependent

1. Membrane currents have been examined in the cell body of the fast coxal depressor motor neuron (Df) of the cockroach Periplaneta americana with the use of two-electrode voltage clamp. 2. Most of the outward current induced by membrane depolarizations to between -40 and +80 mV was carried by K+ because it was blocked by external tetraethylammonium+ (TEA+; 20 mM) and internal Cs+. 3. Over the potential range -20 to +80 mV, a large proportion of this TEA+/Cs(+)-sensitive K+ current consisted of two temporal components, a transient outward current (IKtrans) and a sustained outward current (IKsus). IKtrans and a large proportion of IKsus appeared to be calcium-activated potassium currents (IK,Ca,trans and IK,Ca,sus, respectively) because these were suppressed by injecting ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), removing Ca2+ from the saline or replacing Ca2+ with Ba2+. After suppression of IK,Ca by internal EGTA or Ca(2+)-free saline, membrane depolarizations positive to -40 mV induced voltage-dependent outward currents (IK,V), which consisted of single-component outward relaxations. 4. When outward currents were blocked by external TEA+/internal Cs+, a voltage-dependent inward current consisting of a transient and a sustained component was observed over the potential range -40 to +40 mV. Both components of this inward current appeared to be carried by Ca2+ because they were blocked by external Cd2+ (1 mM), verapamil (0.1 mM), nifedipine (0.1 mM), or diltiazem (0.1 mM). 5. Both the transient component of the calcium current (ICa,trans) and the sustained component (ICa,sus) were maximal at 0 mV and present when Ca2+ in the saline were replaced by Ba2+. The inactivation of ICa,trans is voltage dependent, the rate of inactivation increasing with membrane depolarization. 6. The current-voltage relationships of Ca2+ currents differed from those of calcium-activated K+ currents. It is proposed that the discrepancy between these current-voltage relationships arises from the rapidity with which IK,Ca is saturated by Ca2+ entering through voltage-dependent channels and because the apparent reversal potential for ICa is not at ECa. 7. Although the similarity in the shape of IK,Ca and ICa might suggest that the time course of IK,Ca is determined by the kinetics of ICa, this appears unlikely in view of the rapid saturation of IK,Ca by Ca2+, which considerably outlasts the period of Ca2+ influx.

Hodgkin-Huxley and partially coupled inactivation models yield different voltage dependence of block

1997 ◽  
Vol 272 (4) ◽  
pp. H2013-H2022 ◽  
Author(s):  
S. Liu ◽  
R. L. Rasmusson
Keyword(s):  
Voltage Dependence ◽  
Channel Model ◽  
Outward Current ◽  
Blocking Agent ◽  
K Channel ◽  
Transient Outward Current ◽  
Channel Blockers ◽  
Channel Block ◽  
Current Channel ◽  
Voltage Dependent

K+ channel blockers have been shown to exhibit complex time- and voltage-dependent effects on cardiac K+ currents. Whereas much attention has been focused on the state dependence of K+ channel block, how a particular channel model can alter the predicted time and voltage dependence of channel block remains unexplored. In this study, using two different model formalisms for the same cardiac transient outward current channel, we compare the effects of a theoretical open-state specific channel blocker on macroscopic currents. Model 1 is a Hodgkin-Huxley-like model, in which inactivation is an intrinsically voltage-dependent process and occurs independently of activation. Model 2 is a "partially coupled" model, in which inactivation is intrinsically voltage insensitive but requires channel activation before it can proceed. In the absence of drug (blocking agent), the two models reproduce the macroscopic current data. In the presence of blocking agent, the two models can differ substantially, with model 1 displaying much less block than model 2. We also examine simple mathematically convenient modifications to the Hodgkin-Huxley formalism, which reproduce some, but not all, of the use-dependent properties of block. Thus model formalism is important for analysis and simulation of state-specific drug-channel interactions.

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