Ionic currents in vertebrate myelinated nerve at hyperbaric pressure

1984 ◽  
Vol 246 (1) ◽  
pp. C84-C90 ◽  
Author(s):  
J. J. Kendig
Keyword(s):  
Steady State ◽  
Sodium Current ◽  
Ionic Currents ◽  
Base Line ◽  
Myelinated Nerve ◽  
Hyperbaric Pressure ◽  
Voltage Curve ◽  
Current Voltage ◽  
Voltage Dependent ◽  
Steady State Inactivation

To establish a base line for a study of anesthetic-pressure antagonism in axons, voltage-clamped nodes of Ranvier from amphibian sciatic nerve were subjected to pressures of 1-100 atm. Over the time of compression, there was usually an irreversible decrease in peak inward sodium current, but there was no change in peak outward sodium current or in the current-voltage relationship. The steady-state inactivation-voltage curve was shifted 5-15 mV in the depolarizing direction at 70-100 atm. The rate of rise of the sodium current was slowed, as was the time constant of inactivation (tau h). Increase in tau h was markedly voltage dependent, suggesting a selective effect of pressure on beta h, the rate constant governing development of the inactive state. The rate of development of steady-state outward potassium current was also decreased, without significant change in maximum current. The effects of pressure are qualitatively similar to, but different in detail from, those reported in squid axon and different in some details from the effects of cooling in this preparation. None of the effects can presently be related to the high-pressure nervous syndrome.

scholarly journals Inactivation of the Sodium Current in Myxicola Giant Axons

1972 ◽  
Vol 59 (6) ◽  
pp. 659-675 ◽  
Author(s):  
L. Goldman ◽  
C. L. Schauf
Keyword(s):  
Steady State ◽  
Sodium Current ◽  
Voltage Characteristic ◽  
Current Voltage Characteristic ◽  
Inactivation Curve ◽  
Giant Axons ◽  
Sodium Conductance ◽  
Current Voltage ◽  
Steady State Inactivation ◽  
The Right

Experiments were conducted on Myxicola giant axons to determine if the sodium activation and inactivation processes are coupled or independent. The main experimental approach was to examine the effects of changing test pulses on steady-state inactivation curves. Arguments were presented to show that in the presence of a residual uncompensated series resistance the interpretation of the results depends critically on the manner of conducting the experiment. Analytical and numerical calculations were presented to show that as long as test pulses are confined to an approximately linear negative conductance region of the sodium current-voltage characteristic, unambiguous interpretations can be made. When examined in the manner of Hodgkin and Huxley, inactivation in Myxicola is quantitatively similar to that described by the h variable in squid axons. However, when test pulses were increased along the linear negative region of the sodium current-voltage characteristic, steady-state inactivation curves translate to the right along the voltage axis. The shift in the inactivation curve is a linear function of the ratio of the sodium, conductance of the test pulses, showing a 5.8 mv shift for a twofold increase in conductance. An independent line of evidence indicated that the early rate of development of inactivation is a function of the rise of the sodium conductance.

Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded α1A in SCA6

2007 ◽  
Vol 292 (3) ◽  
pp. C1078-C1086 ◽  
Author(s):  
Haiyan Chen ◽  
Erika S. Piedras-Rentería
Keyword(s):  
Steady State ◽  
Late Onset ◽  
Spinocerebellar Ataxia Type ◽  
Gain Of Function ◽  
Calcium Dependent ◽  
Spinocerebellar Ataxia Type 6 ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Activity Dependent

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease of the cerebellum and inferior olives characterized by a late-onset cerebellar ataxia and selective loss of Purkinje neurons ( 15 , 16 ). SCA6 arises from an expansion of the polyglutamine tract located in exon 47 of the α1A (P/Q-type calcium channel) gene from a nonpathogenic size of 4 to 18 glutamines (CAG4–18) to CAG19–33 in SCA6. The molecular basis of SCA6 is poorly understood. To date, the biophysical properties studied in heterologous systems support both a gain and a loss of channel function in SCA6. We studied the behavior of the human α1A isoform, previously found to elicit a gain of function in disease ( 41 ), focusing on properties in which the COOH terminus of the channel is critical for function: we analyzed the current properties in the presence of β4- and β2a-subunits (both known to interact with the α1A COOH terminus), current kinetics of activation and inactivation, calcium-dependent inactivation and facilitation, voltage-dependent inactivation, frequency dependence, and steady-state activation and inactivation properties. We found that SCA6 channels have decreased activity-dependent inactivation and a depolarizing shift (+6 mV) in steady-state inactivation properties consistent with a gain of function.

Single calcium channels in resistance-sized cerebral arteries from rats

1993 ◽  
Vol 264 (2) ◽  
pp. H470-H478 ◽  
Author(s):  
J. M. Quayle ◽  
J. G. McCarron ◽  
J. R. Asbury ◽  
M. T. Nelson
Keyword(s):  
Steady State ◽  
Calcium Channels ◽  
Single Channel ◽  
Cerebral Arteries ◽  
Membrane Depolarization ◽  
Barium Concentration ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Wistar Kyoto ◽  
Single Calcium Channels

Unitary currents through single calcium channels were measured from cell-attached patches on smooth muscle cells isolated from resistance-sized branches of posterior cerebral arteries from Wistar-Kyoto normotensive rats. Barium (80 and 10 mM) was used as the charge carrier, with and without the dihydropyridine calcium channel agonist BAY R 5417. Unitary currents decreased on membrane depolarization, with a slope conductance of 19.4 pS (80 mM barium). Channel open-state probability (Po) was steeply voltage dependent. Peak Po during test pulses from -70 mV increased e-fold per 4.5-mV depolarization. Mean peak Po at potentials positive to +10 mV was 0.44. Po at steady membrane potentials was also steeply voltage dependent, changing e-fold per 4.5 mV in the absence of inactivation. Steady-state Po at positive potentials was substantially lower than peak Po elicited by test pulses, suggesting that steady-state inactivation can reduce Po by as much as 10-fold. Membrane depolarization decreased the longest mean closed time but had little effect on the mean open time of single calcium channels measured during steady-state recordings. Lowering the external barium concentration from 80 to 10 mM reduced the single channel conductance to 12.4 pS and shifted the relationship between steady-state Po and membrane potential by about -30 mV. BAY R 5417 also shifted this relationship by about -15 mV.

scholarly journals Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

1985 ◽  
Vol 86 (5) ◽  
pp. 739-762 ◽  
Author(s):  
G K Wang ◽  
G Strichartz
Keyword(s):  
Steady State ◽  
Ionic Currents ◽  
Na Channel ◽  
Dependent Manner ◽  
Na Current ◽  
Toxin Concentration ◽  
Toxin Molecule ◽  
Channel Inactivation ◽  
Na Currents ◽  
Voltage Dependent

The effects of a neurotoxin, purified from the venom of the scorpion Leiurus quinquestriatus, on the ionic currents of toad single myelinated fibers were studied under voltage-clamp conditions. Unlike previous investigations using crude scorpion venom, purified Leiurus toxin II alpha at high concentrations (200-400 nM) did not affect the K currents, nor did it reduce the peak Na current in the early stages of treatment. The activation of the Na channel was unaffected by the toxin, the activation time course remained unchanged, and the peak Na current vs. voltage relationship was not altered. In contrast, Na channel inactivation was considerably slowed and became incomplete. As a result, a steady state Na current was maintained during prolonged depolarizations of several seconds. These steady state Na currents had a different voltage dependence from peak Na currents and appeared to result from the opening of previously inactivated Na channels. The opening kinetics of the steady state current were exponential and had rates approximately 100-fold slower than the normal activation processes described for transitions from the resting state to the open state. In addition, the dependence of the peak Na current on the potential of preceding conditioning pulses was also dramatically altered by toxin treatment; this parameter reached a minimal value near a membrane potential of -50 mV and then increased continuously to a "plateau" value at potentials greater than +50 mV. The amplitude of this plateau was dependent on toxin concentration, reaching a maximum value equal to approximately 50% of the peak current; voltage-dependent reversal of the toxin's action limits the amplitude of the plateauing effect. The measured plateau effect was half-maximum at a toxin concentration of 12 nM, a value quite similar to the concentration producing half of the maximum slowing of Na channel inactivation. The results of Hill plots for these actions suggest that one toxin molecule binds to one Na channel. Thus, the binding of a single toxin molecule probably both produces the steady state currents and slows the Na channel inactivation. We propose that Leiurus toxin inhibits the conversion of the open state to inactivated states in a voltage-dependent manner, and thereby permits a fraction of the total Na permeability to remain at membrane potentials where inactivation is normally complete.

The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Nav1.6 voltage-dependent sodium channel

2007 ◽  
Vol 293 (2) ◽  
pp. C783-C789 ◽  
Author(s):  
Christian Rosker ◽  
Birgit Lohberger ◽  
Doris Hofer ◽  
Bibiane Steinecker ◽  
Stefan Quasthoff ◽  
...  
Keyword(s):  
Steady State ◽  
Sodium Channels ◽  
Therapeutic Intervention ◽  
Time Course ◽  
Specific Interaction ◽  
Xenopus Laevis Oocytes ◽  
Recovery From Inactivation ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Invaluable Tool

The blocking efficacy of 4,9-anhydro-TTX (4,9-ah-TTX) and TTX on several isoforms of voltage-dependent sodium channels, expressed in Xenopus laevis oocytes, was tested (Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, and Nav1.8). Generally, TTX was 40–231 times more effective, when compared with 4,9-ah-TTX, on a given isoform. An exception was Nav1.6, where 4,9-ah-TTX in nanomole per liter concentrations sufficed to result in substantial block, indicating that 4,9-ah-TTX acts specifically at this peculiar isoform. The IC50 values for TTX/4,9-ah-TTX were as follows (in nmol/l): 7.8 ± 1.3/1,260 ± 121 (Nav1.2), 2.8 ± 2.3/341 ± 36 (Nav1.3), 4.5 ± 1.0/988 ± 62 (Nav1.4), 1,970 ± 565/78,500 ± 11,600 (Nav1.5), 3.8 ± 1.5/7.8 ± 2.3 (Nav1.6), 5.5 ± 1.4/1,270 ± 251 (Nav1.7), and 1,330 ± 459/>30,000 (Nav1.8). Analysis of approximal half-maximal doses of both compounds revealed minor effects on voltage-dependent activation only, whereas steady-state inactivation was shifted to more negative potentials by both TTX and 4,9-ah-TTX in the case of the Nav1.6 subunit, but not in the case of other TTX-sensitive ones. TTX shifted steady-state inactivation also to more negative potentials in case of the TTX-insensitive Nav1.5 subunit, where it also exerted profound effects on the time course of recovery from inactivation. Isoform-specific interaction of toxins with ion channels is frequently observed in the case of proteinaceous toxins. Although the sensitivity of Nav1.1 to 4,9-ah-TTX is not known, here we report evidence on a highly isoform-specific TTX analog that may well turn out to be an invaluable tool in research for the identification of Nav1.6-mediated function, but also for therapeutic intervention.

scholarly journals Voltage-dependent inactivation of slow calcium channels in intact twitch muscle fibers of the frog.

1989 ◽  
Vol 94 (5) ◽  
pp. 937-951 ◽  
Author(s):  
G Cota ◽  
E Stefani
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Voltage Dependence ◽  
Muscle Fibers ◽  
Dependent Manner ◽  
Inactivation Curve ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Intact Muscle ◽  
Ca2 Channels

Inactivation of slow Ca2+ channels was studied in intact twitch skeletal muscle fibers of the frog by using the three-microelectrode voltage-clamp technique. Hypertonic sucrose solutions were used to abolish contraction. The rate constant of decay of the slow Ca2+ current (ICa) remained practically unchanged when the recording solution containing 10 mM Ca2+ was replaced by a Ca2+-buffered solution (126 mM Ca-maleate). The rate constant of decay of ICa monotonically increased with depolarization although the corresponding time integral of ICa followed a bell-shaped function. The replacement of Ca2+ by Ba2+ did not result in a slowing of the rate of decay of the inward current nor did it reduce the degree of steady-state inactivation. The voltage dependence of the steady-state inactivation curve was steeper in the presence of Ba2+. In two-pulse experiments with large conditioning depolarizations ICa inactivation remained unchanged although Ca2+ influx during the prepulse greatly decreased. Dantrolene (12 microM) increased mechanical threshold at all pulse durations tested, the effect being more prominent for short pulses. Dantrolene did not significantly modify ICa decay and the voltage dependence of inactivation. These results indicate that in intact muscle fibers Ca2+ channels inactivate in a voltage-dependent manner through a mechanism that does not require Ca2+ entry into the cell.

Dual actions of caffeine on voltage-dependent currents and intracellular calcium in taste receptor cells

2002 ◽  
Vol 283 (1) ◽  
pp. R115-R129 ◽  
Author(s):  
Fang-Li Zhao ◽  
Shao-Gang Lu ◽  
Scott Herness
Keyword(s):  
Intracellular Calcium ◽  
Imaging Techniques ◽  
Sodium Current ◽  
Taste Receptor ◽  
Input Resistance ◽  
Ionic Currents ◽  
Receptor Cells ◽  
Voltage Dependent ◽  
Transduction Mechanisms ◽  
Taste Receptor Cells

Although the numerous stimuli representing the taste quality of bitterness are known to be transduced through multiple mechanisms, recent studies have suggested an unpredicted complexity of the transduction pathways for individual bitter stimuli. To investigate this notion more thoroughly, a single prototypic bitter stimulus, caffeine, was studied by using patch-clamp and ratiometric imaging techniques on dissociated rat taste receptor cells. At behaviorally relevant concentrations, caffeine produced strong inhibition of outwardly and inwardly rectifying potassium currents. Caffeine additionally inhibited calcium current, produced a weaker inhibition of sodium current, and was without effect on chloride current. Consistent with its effects on voltage-dependent currents, caffeine caused a broadening of the action potential and an increase of the input resistance. Caffeine was an effective stimulus for elevation of intracellular calcium. This elevation was concentration dependent, independent of extracellular calcium or ryanodine, and dependent on intracellular stores as evidenced by thapsigargin treatment. These dual actions on voltage-activated ionic currents and intracellular calcium levels suggest that a single taste stimulus, caffeine, utilizes multiple transduction mechanisms.

scholarly journals The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. I. Basic characterization and kinetic analysis.

1993 ◽  
Vol 101 (4) ◽  
pp. 571-601 ◽  
Author(s):  
D L Campbell ◽  
R L Rasmusson ◽  
Y Qu ◽  
H C Strauss
Keyword(s):  
Steady State ◽  
Ventricular Myocytes ◽  
Nonlinear Least Squares ◽  
Patch Clamp Technique ◽  
Time Constants ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
K Current ◽  
Necessary And Sufficient

Enzymatically isolated myocytes from ferret right ventricles (12-16 wk, male) were studied using the whole cell patch clamp technique. The macroscopic properties of a transient outward K+ current I(to) were quantified. I(to) is selective for K+, with a PNa/PK of 0.082. Activation of I(to) is a voltage-dependent process, with both activation and inactivation being independent of Na+ or Ca2+ influx. Steady-state inactivation is well described by a single Boltzmann relationship (V1/2 = -13.5 mV; k = 5.6 mV). Substantial inactivation can occur during a subthreshold depolarization without any measurable macroscopic current. Both development of and recovery from inactivation are well described by single exponential processes. Ensemble averages of single I(to) channel currents recorded in cell-attached patches reproduce macroscopic I(to) and indicate that inactivation is complete at depolarized potentials. The overall inactivation/recovery time constant curve has a bell-shaped potential dependence that peaks between -10 and -20 mV, with time constants (22 degrees C) ranging from 23 ms (-90 mV) to 304 ms (-10 mV). Steady-state activation displays a sigmoidal dependence on membrane potential, with a net aggregate half-activation potential of +22.5 mV. Activation kinetics (0 to +70 mV, 22 degrees C) are rapid, with I(to) peaking in approximately 5-15 ms at +50 mV. Experiments conducted at reduced temperatures (12 degrees C) demonstrate that activation occurs with a time delay. A nonlinear least-squares analysis indicates that three closed kinetic states are necessary and sufficient to model activation. Derived time constants of activation (22 degrees C) ranged from 10 ms (+10 mV) to 2 ms (+70 mV). Within the framework of Hodgkin-Huxley formalism, Ito gating can be described using an a3i formulation.

scholarly journals Inhibition of Kv4.3 by genistein via a tyrosine phosphorylation-independent mechanism

2011 ◽  
Vol 300 (3) ◽  
pp. C567-C575 ◽  
Author(s):  
Hee Jae Kim ◽  
Hye Sook Ahn ◽  
Bok Hee Choi ◽  
Sang June Hahn
Keyword(s):  
Steady State ◽  
Inactivation Kinetics ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Inactivation Curve ◽  
Voltage Range ◽  
Closed State ◽  
Voltage Dependent ◽  
Dependent Inhibition ◽  
Steady State Inactivation

The effects of genistein, a protein tyrosine kinase (PTK) inhibitor, on voltage-dependent K+ (Kv) 4.3 channel were examined using the whole cell patch-clamp techniques. Genistein inhibited Kv4.3 in a reversible, concentration-dependent manner with an IC50 of 124.78 μM. Other PTK inhibitors (tyrphostin 23, tyrphostin 25, lavendustin A) had no effect on genistein-induced inhibition of Kv4.3. Orthovanadate, an inhibitor of protein phosphatases, did not reverse the inhibition of Kv4.3 by genistein. We also tested the effects of two inactive structural analogs: genistin and daidzein. Whereas Kv4.3 was unaffected by genistin, daidzein inhibited Kv4.3, albeit with a lower potency. Genistein did not affect the activation and inactivation kinetics of Kv4.3. Genistein-induced inhibition of Kv4.3 was voltage dependent with a steep increase over the channel opening voltage range. In the full-activation voltage range positive to +20 mV, no voltage-dependent inhibition was found. Genistein had no significant effect on steady-state activation, but shifted the voltage dependence of the steady-state inactivation of Kv4.3 in the hyperpolarizing direction in a concentration-dependent manner. The Ki for the interaction between genistein and the inactivated state of Kv4.3, which was estimated from the concentration-dependent shift in the steady-state inactivation curve, was 1.17 μM. Under control conditions, closed-state inactivation was fitted to a single exponential function, and genistein accelerated closed-state inactivation. Genistein induced a weak use-dependent inhibition. These results suggest that genistein directly inhibits Kv4.3 by interacting with the closed-inactivated state of Kv4.3 channels. This effect is not mediated via inhibition of the PTK activity, because other types of PTK inhibitors could not prevent the inhibitory action of genistein.

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