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1.
Complex nonlinear dynamics of the Hodgkin-Huxley equations induced by time scale changes 总被引:3,自引:0,他引:3
The Hodgkin–Huxley equations with a slight modification are investigated, in which the inactivation process (h) of sodium channels or the activation process of potassium channels (n) is slowed down. We show that the equations produce a variety of action potential waveforms ranging from a plateau potential,
such as in heart muscle cells, to chaotic bursting firings. When h is slowed down – differently from the case of n variable being slow – chaotic bursting oscillations are observed for a wide range of parameter values although both variables
cause a decrease in the membrane potential. The underlying nonlinear dynamics of various action potentials are analyzed using
bifurcation theory and a so-called slow–fast decomposition analysis. It is shown that a simple topological property of the
equilibrium curves of slow and fast subsystems is essential to the production of chaotic oscillations, and this is the cause
of the large difference in global firing characteristics between the h-slow and n-slow cases.
Received: 9 August 2000 / Accepted in revised form: 10 January 2001 相似文献
2.
The potassium A-current,low firing rates and rebound excitation in Hodgkin-Huxley models 总被引:3,自引:0,他引:3
It is widely believed, following the work of Connor and Stevens (1971,J. Physiol. Lond.
214, 31–53) that the ability to fire action potentials over a wide frequency range, especially down to very low rates, is due
to the transient, potassium A-current (I
A). Using a reduction of the classical Hodgkin-Huxley model, we study the effects ofI
A on steady firing rate, especially in the near-threshold regime for the onset of firing. A minimum firing rate of zero corresponds
to a homoclinic bifurcation of periodic solutions at a critical level of stimulating current. It requires that the membrane's
steady-state current-voltage relation be N-shaped rather than monotonic. For experimentally based genericI
A parameters, the model does not fire at arbitrarily low rates, although it can for the more atypicalI
A parameters given by Connor and Stevens for the crab axon. When theI
A inactivation rate is slow, we find that the transient potassium current can mediate more complex firing patterns, such as
periodic bursting in some parameter regimes. The number of spikes per burst increases asg
A decreases and as inactivation rate decreases. We also study howI
A affects properties of transient voltage responses, such as threshold and firing latency for anodal break excitation. We provide
mathematical explanations for several of these dynamic behaviors using bifurcation theory and averaging methods. 相似文献
3.
The effects of sodium metabisulfite (SMB), a general food preservative, on potassium currents in rat dorsal root ganglion
(DRG) neurons were investigated using the whole-cell patch-clamp technique. SMB increased the amplitudes of both transient
outward potassium currents and delayed rectifier potassium current in concentration- and voltage-dependent manner. The transient
outward potassium currents (TOCs) include a fast inactivating (A-current or I
A) current and a slow inactivating (D-current or I
D) current. SMB majorly increased IA, and ID was little affected. SMB did not affect the activation process of transient outward currents (TOCs), but the inactivation
curve of TOCs was shifted to more positive potentials. The inactivation time constants of TOCs were also increased by SMB.
For delayed rectifier potassium current (I
K), SMB shifted the activation curve to hyperpolarizing direction. SMB differently affected TOCs and I
K, its effects major on A-type K+ channels, which play a role in adjusting pain sensitivity in response to peripheral redox conditions. SMB did not increase
TOCs and I
K when adding DTT in pipette solution. These results suggested that SMB might oxidize potassium channels, which relate to adjusting
pain sensitivity in pain-sensing DRG neurons. 相似文献
4.
Eric Jakobsson 《Journal of mathematical biology》1978,6(3):235-248
Summary The axon membrane is simulated by standard Hodgkin-Huxley leakage and potassium channels plus a coupled transient excited
state kinetic scheme for the sodium channel. This scheme for the sodium channel is as proposed previously by the author. Simultations
are presented showing the form of the action potential, threshold behavior, accommodation, and repetitive firing. It is seen
that the form of the individual action potential, its all-or-none nature, and its refractory period are well simulated by
this model, as they are by the standard Hodgkin-Huxley model. However, the model differs markedly from the Hodgkin-Huxley
model with respect to repetitive firing and accommodation to stimulating currents of slowly rising intensity, in ways that
are anomn to be related to those features of the sodium inactivation which are anomalous to the H-H model. The tendency for
repetitive firing is highly dependent on that parameter which primarily determintes the existence of the inactivation shift
in voltage clamp experiments, in such a way that the more pronounced the inactivation shift, the less the tendency for repetitive
firing,. The tendency for accommodation is highly dependent on that parameter which primarily determines the “τc − τh” separation, in such a way that the greater the separation the greater the tendency for the membrane to accommodate without
firing action potentials to a slowly rising current. 相似文献
5.
I. V. Melnick 《Neurophysiology》2011,42(4):239-243
Upon application of a long-lasting rectangular stimulus, neurons of the substantia gelatinosa (SG) display three main types of intrinsic firing behavior, tonic, adapting, and delayed onset. The electrical landmark of delayed-firing
neurons (DFNs), i.e., a significant delay before initiation of action potentials (APs), is believed to result from activation
of subthreshold A-type K+ current (KA). We checked out this hypothesis by comparing the voltage dependence of the firing delay with steady-state inactivation of
KA in spinal cord slices of 3- to 5-week-old rats. The delay strongly decreased with membrane depolarization and disappeared
at ~ –60 mV; herewith the discharge pattern was transformed to either a tonic or an adapting one. This correlated well with
inactivation of KA recorded in a whole-cell mode in low-Cl– intracellular solution; inactivation was nearly complete at –60 mV (voltage of half-maximum inactivation, V
1/2 ~ –74.5 mV). Unexpectedly, it was found that filling the cells with high-Cl– solution, to minimize the liquid junction potential, produced at least a 10 mV-difference between voltage dependences of
the firing delay and KA inactivation; the latter shifted toward negativity (V
1/2 ~ –88.3 mV). The results suggest that the KA and its inactivation properties determine the appearance and voltage dependence of the firing delay in SG neurons; the apparent influence of intracellular Cl– on inactivation properties needs further investigation. 相似文献
6.
David K. Jones Colin H. Peters Charlene R. Allard Tom W. Claydon Peter C. Ruben 《The Journal of biological chemistry》2013,288(7):4782-4791
Protons impart isoform-specific modulation of inactivation in neuronal, skeletal muscle, and cardiac voltage-gated sodium (NaV) channels. Although the structural basis of proton block in NaV channels has been well described, the amino acid residues responsible for the changes in NaV kinetics during extracellular acidosis are as yet unknown. We expressed wild-type (WT) and two pore mutant constructs (H880Q and C373F) of the human cardiac NaV channel, NaV1.5, in Xenopus oocytes. C373F and H880Q both attenuated proton block, abolished proton modulation of use-dependent inactivation, and altered pH modulation of the steady-state and kinetic parameters of slow inactivation. Additionally, C373F significantly reduced the maximum probability of use-dependent inactivation and slow inactivation, relative to WT. H880Q also significantly reduced the maximum probability of slow inactivation and shifted the voltage dependence of activation and fast inactivation to more positive potentials, relative to WT. These data suggest that Cys-373 and His-880 in NaV1.5 are proton sensors for use-dependent and slow inactivation and have implications in isoform-specific modulation of NaV channels. 相似文献
7.
Summary Fast inactivation and deactivation gating were compared between wild-type human voltage-gated skeletal muscle sodium channel
(hNaV1.4) and potassium-aggravated myotonia (PAM) mutations G1306A, G1306E, and G1306V. Cell-attached macropatches were used to
compare wild-type and PAM-gating properties in normal extracellular K+ (4 mM), decreased K+ (1 mM), and increased K+ (10 mM). G1306E/A increased the apparent valence of the conductance (g(V)) curve. Compared to hNaV1.4, the steady-state inactivation (h∞) curve was depolarized for G1306E/A but hyperpolarized by G1306V, and this mutation increased apparent valence. G1306A/E
slowed the rate of current rise towards peak activation. G1306V slowed open-state deactivation, inactivated-state deactivation,
and recovery from fast inactivation. G1306A/E abbreviated open-state deactivation at negative commands. These mutants slowed
open-state deactivation at more positive commands, at voltages for which fast inactivation might influence tail current decay.
G1306E abbreviated recovery delay without affecting recovery rate. Low K+ increased peak current in hNaV1.4 and in G1306V. For G1306E, low K+ increased the rate of entry into fast inactivation, hyperpolarized the g(V) and h∞ curves, and increased recovery delay. Biophysical underpinnings of PAM caused by mutations of G1306 thus vary with the specific
mutation, and hyperkalemic exacerbation of effects of mutations at this residue are not direct. 相似文献
8.
In the work reported here, we have investigated the changes in the activation and fast inactivation properties of the rat
brain voltage-gated sodium channel (rNav 1.2a) α subunit, expressed heterologously in the Chinese Hamster Ovary (CHO) cells, by short depolarizing prepulses (10 –
1000 ms). The time constant of recovery from fast inactivation (τfast) and steady-state parameters for activation and inactivation varied in a pseudo-oscillatory fashion with the duration and
amplitude of a sustained prepulse. A consistent oscillation was observed in most of the steady-state and non-inactivating
current parameters with a time period close to 225 ms, although a faster oscillation of time period 125 ms was observed in
the τfast. The studies on the non-inactivating current and steady-state activation indicate that the phase of oscillation varies from
cell to cell. Co-expression of the β1 subunit with the α subunit channel suppressed the oscillation in the charge movement
per single channel and free energy of steady-state inactivation, although the oscillation in the half steady-state inactivation
potential remained unaltered. Incidentally, the frequencies of oscillation in the sodium channel parameters (4–8 Hz) correspond
to the theta component of network oscillation. This fast pseudo-oscillatory mechanism, together with the slow pseudo-oscillatory
mechanism found in these channels earlier, may contribute to the oscillations in the firing properties observed in various
neuronal subtypes and many pathological conditions. 相似文献
9.
Evyatar Av-Ron 《Journal of mathematical biology》1994,33(1):71-87
Presented here is a biophysical cell model which can exhibit low-frequency repetitive activity and bursting behavior. The
model is developed from previous models (Av-Ron et al. 1991, 1993) for excitability, oscillations and bursting. A stepwise
development of the present model shows the contribution of a transient potassium current (I
A
) to the overall dynamics. By changing a limited set of model parameters one can describe different firing patterns; oscillations
with frequencies ranging from 2–200 Hz and a wide range of bursting behaviors in terms of the durations of bursting and quiescence,
peak firing frequency and rate of change of the firing frequency. 相似文献
10.
《Channels (Austin, Tex.)》2013,7(1):46-56
KV2.1 is the prominent somatodendritic sustained or delayed rectifier voltage-gated potassium (Kv) channel in mammalian central neurons, and is a target for activity-dependent modulation via calcineurin-dependent dephosphorylation. Using hanatoxin-mediated block of KV2.1 we show that, in cultured rat hippocampal neurons, glutamate stimulation leads to significant hyperpolarizing shifts in the voltage-dependent activation and inactivation gating properties of the KV2.1-component of delayed rectifier K+ (IK) currents. In computer models of hippocampal neurons, these glutamate-stimulated shifts in the gating of the KV2.1-component of IK lead to a dramatic suppression of action potential firing frequency. Current-clamp experiments in cultured rat hippocampal neurons showed glutamate-stimulation induced a similar suppression of neuronal firing frequency. Membrane depolarization also resulted in similar hyperpolarizing shifts in the voltage-dependent gating properties of neuronal IK currents, and suppression of neuronal firing. The glutamate-induced effects on neuronal firing were eliminated by hanatoxin, but not by dendrotoxin-K, a blocker of KV1.1-containing channels. These studies together demonstrate a specific contribution of modulation of KV2.1 channels in the activity-dependent regulation of intrinsic neuronal excitability. 相似文献
11.
Groome JR Alexander HM Fujimoto E Sherry M Petty D 《Cellular and molecular neurobiology》2007,27(1):87-106
Summary 1. Mutations in the S4 segment of domain III in the voltage gated skeletal muscle sodium channel hNaV1.4 were constructed to test the roles of each charged residue in deactivation gating. Mutations comprised charge reversals
at K1-R6, charge neutralization, and substitution at R4 and R5.
2. Charge-reversing mutations at R4 and R5 produced the greatest alteration of activation parameters compared to hNaV1.4. Effects included depolarization of the conductance/voltage (g/V) curve, decreased valence and slowing of kinetics.
3. Reversal of charge at R2 to R4 hyperpolarized, and reversal at R5 or R6 depolarized the h
∞ curve. Most DIIIS4 mutations slowed inactivation from the open state. R4E slowed closed state fast inactivation and R5E inhibited
its completion.
4. Deactivation from the open and/or inactivated state was prolonged in mutations reversing charge at R2 to R4 but accelerated
by reversal of charge at R5 or R6. Effects were most pronounced at central charges R4 and R5.
5. Charge and structure each contribute to effects of mutations at R4 and R5 on channel gating. Effects of mutations on activation
and deactivation at R4 and, to a lesser extent R5, were primarily owing to charge alteration, whereas effects on fast inactivation
were charge independent. 相似文献
12.
Gap junction channels are gated by a chemical gate and two transjunctional voltage (V
j)-sensitive gates: fast and slow. Slow V
j gate and chemical gate are believed to be the same. The slow gate closes at the negative side of V
j and is mostly inactive without uncouplers or connexin (Cx) mutations. In contrast, our present data indicate otherwise. Oocytes
expressing Cx32 were subjected to series of −100 mV
V
j pulses (12-s duration, 30-s intervals). Both peak (PK) and steady-state (SS) junctional conductances (G
j), measured at each pulse, decreased exponentially by 50−60% (tau = ∼1.2 min). G
jPK dropped more dramatically, such that G
jSS/G
jPK increased from 0.4 to 0.6, indicating a drop in V
j sensitivity. Less striking effects were obtained with –60 mV pulses. During recovery, G
j, measured by applying 20 mV pulses (2-s duration, 30-s intervals), slowly returned to initial values (tau = ∼7 min). With reversal of V
j polarity, G
jPK briefly increased and G
jSS/G
jPK decreased, suggesting that V
j-dependent hemichannel reopening is faster than hemichannel closing. Similar yet more dramatic results were obtained with
COOH-terminus truncated Cx32 (Cx32-D225), a mutant believed to lack fast V
j gating. The data indicate that the slow gate of Cx32 is active in the absence of uncouplers or mutations and displays unusual
V
j behavior. Based on previous evidence for direct calmodulin (CaM) involvement in chemical/slow gating, this may also be CaM-mediated. 相似文献
13.
The interpretation of slow inactivation in potassium channels has been strongly influenced by work on C-type inactivation in Shaker channels. Slow inactivation in Shaker and some other potassium channels can be dramatically modulated by the state of the pore, including mutations at outer pore residue T449, which altered inactivation kinetics up to 100-fold. KV2.1, another voltage-dependent potassium channel, exhibits a biophysically distinct inactivation mechanism with a U-shaped voltage-dependence and preferential closed-state inactivation, termed U-type inactivation. However, it remains to be demonstrated whether U-type and C-type inactivation have different molecular mechanisms. This study examines mutations at Y380 (homologous to Shaker T449) to investigate whether C-type and U-type inactivation have distinct molecular mechanisms, and whether C-type inactivation can occur at all in KV2.1. Y380 mutants do not introduce C-type inactivation into KV2.1 and have little effect on U-type inactivation of KV2.1. Interestingly, two of the mutants tested exhibit twofold faster recovery from inactivation compared to wild-type channels. The observation that mutations have little effect suggests KV2.1 lacks C-type inactivation as it exists in Shaker and that C-type and U-type inactivation have different molecular mechanisms. Kinetic modeling predicts that all mutants inactivate preferentially, but not exclusively, from partially activated closed states. Therefore, KV2.1 exhibits a single U-type inactivation process including some inactivation from open as well as closed states. 相似文献
14.
Yoshinobu Maeda K. Pakdaman Taishin Nomura Shinji Doi Shunsuke Sato 《Biological cybernetics》1998,78(4):265-276
The eight-variable model for the giant neuron localized in the esophageal ganglia of the marine pulmonate mollusk Onchidium verruculatum is reduced to four-and-three-dimensional systems by regrouping variables with similar time scales. These reduced models replicate
the complex behavior including beating, periodic bursting and aperiodic bursting displayed by the original full model when
the parameter I
ext
representing the intensity of the constant DC current stimulation is varied across a wide range. The complex behavior of
the full model arises from the interaction of fast and slow dynamics, and depends on the time scale C
s
of the slow dynamics. The four-variable reduced model is constructed independently from the parameter C
s
so that it reproduces the two-dimensional bifurcation structure of the full model for the two parameters I
ext
and C
s
. The three-variable reduced model is derived for a specific value of C
s
. The parameters of this model are tuned so that its one-parameter bifurcation diagram for I
ext
closely matches that of the full model. Correspondence between bifurcation structures ensures that both reduced models reproduce
the various discharge patterns of the full model. Similarity between the full and reduced models is also confirmed by comparing
mean firing frequencies and membrane potential waveforms in various regimes. The reduction exposes the factors essential for
reproducing the dynamics of the full model; indeed, it shows that the eight variables representing the membrane potential
and seven gating variables of six ionic currents in the full model account, in fact, for three basic processes responsible
for excitability, post-discharge refractoriness and slow membrane modulation.
Received: 7 May 1996 / Accepted 4 December 1997 相似文献
15.
Antonios G. Dougalis Gillian A. C. Matthews Birgit Liss Mark A. Ungless 《Journal of computational neuroscience》2017,42(3):275-305
Dopamine (DA) neurons of the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) fire spontaneous action potentials (APs) at slow, regular patterns in vitro but a detailed account of their intrinsic membrane properties responsible for spontaneous firing is currently lacking. To resolve this, we performed a voltage-clamp electrophysiological study in brain slices to describe their major ionic currents and then constructed a computer model and used simulations to understand the mechanisms behind autorhythmicity in silico. We found that vlPAG/DRN DA neurons exhibit a number of voltage-dependent currents activating in the subthreshold range including, a hyperpolarization-activated cation current (IH), a transient, A-type, potassium current (IA), a background, ‘persistent’ (INaP) sodium current and a transient, low voltage activated (LVA) calcium current (ICaLVA). Brain slice pharmacology, in good agreement with computer simulations, showed that spontaneous firing occurred independently of IH, IA or calcium currents. In contrast, when blocking sodium currents, spontaneous firing ceased and a stable, non-oscillating membrane potential below AP threshold was attained. Using the DA neuron model we further show that calcium currents exhibit little activation (compared to sodium) during the interspike interval (ISI) repolarization while, any individual potassium current alone, whose blockade positively modulated AP firing frequency, is not required for spontaneous firing. Instead, blockade of a number of potassium currents simultaneously is necessary to eliminate autorhythmicity. Repolarization during ISI is mediated initially via the deactivation of the delayed rectifier potassium current, while a sodium background ‘persistent’ current is essentially indispensable for autorhythmicity by driving repolarization towards AP threshold. 相似文献
16.
V. A. Bouryi 《Neurophysiology》1998,30(4-5):301-304
Barium currents through ion channels formed by α1-subunit of L-type Ca2+ channel (I
α1) were recorded from cultured chinese hamster ovary (CHO) cells. The cells were stably transfected with either a cardiac or
a smooth muscle (SM) variant of α1-subunit. TheI
α1 in both cases exhibited similar fast voltage-dependent activation kinetics and slow apparent inactivation kinetics. With
10 mM Ba2+ in the bath solution,I
α1 was activated at potentials more positive than −40 mV, peaked between 0 and +10 mV, and reversed at about +50 mV. In addition
to slow apparent inactivation of inward current, both subunits provided an extremely slow voltage-dependent inactivation at
potentials more positive than −100 mV, with half-maximum inactivation at −43.4 mV for cardiac and −41.4 mV for SM α1-subunits.
The onset of inactivation as well as recovery from this process were within a time range of minutes. The voltage dependence
of steady-state inactivation could be fitted by the sum of two Boltzmann's equations with slope factors of about 12 mV and
5 mV. A less sloped component has its midpoints at −75.6 and −63.7 mV, and a steeper component has its midpoints at −42.8
and −37.7 mV for cardiac and SM α1-subunits, respectively. Relative contribution of the steeper component was higher in both
subunits (0.86 and 0.66 for cardiac and SM subunits, respectively). For comparison, the inactivation curves for 5-sec-long
conditioning prepulses could be fitted by single Boltzmann's distribution with a 20 mV more positive midpoint and a slope
factor of about 13 mV. In contrast to the steady-state inactivation curves, they showed considerable overlap with the steady-state
activation curve. Our results reflect functional consequences of known sequence differences between α1-subunits of the cardiac
and SM L-type Ca2+ channels and could be used in structural modeling of Ca2+ channel gating. In addition, they show that depolarization-induced window current has a transient nature and decays with
the development of extremely slow inactivation. This is the first demonstration that slow inactivation of the L-type Ca2+ channel is an intrinsic property of its α1-subunits. 相似文献
17.
The ERG of the isolated, superfused half-eye of the cephalopod Sepiola atlantica, evoked by a brief (10 s) light flash, has been studied by recording intraretinal potentials with glass microelectrodes. The intensity-response characteristics of the potentials recorded at an electrode fixed at the surface (V
s
) can be fitted by a simple equation derived from an equivalent circuit model based on a sodium conductance increase mechanism. Raising the external potassium level reduces the maximal response (V
m
), but does not alter the half-saturation intensity value (I
0). Reducing external sodium does not affect (V
m
), but increases I
0. Reducing external calcium also does not affect (V
m
), but decreases I
0. These effects are adequately described by the model if it is also assumed (a) that changing the external sodium does not significantly alter the transmembrane sodium gradient, and (b) that sodium and calcium ions compete for the sensitivity control mechanism.Differential-depth recording between the fixed electrode at the surface and another electrode that could be moved into the retina revealed that the two component appearance of the transretinal ERG arose from the superposition of two vitreal-negative waveforms. An initial fast component was mainly recorded in the photoreceptive distal segments while a slow component was prominent in the more proximal regions of the retina. Perfusion with high K+ salines resulted in a decrease in the amplitudes of both fast and slow components of the response whereas reducing external Na+ reduced the amplitude of the fast component at all light intensities but reduced the amplitude of the slow component only at low intensities. The amplitudes of both the fast and slow components increased on reducing external calcium, but the rate of rise and fall of the fast component was independent of external calcium. The rate of rise of the slow component was also independent of the external Ca2+ level but a minimum in the recovery time (t
F
) was shifted to a lower intensity value at lower calcium concentrations. The shift of the minimum was to a higher intensity value with lowered sodium perfusing solutions. On the basis of the differential sensitivity of the two components to ion changes, as well as stimulus intensity and intraretinal distribution of the components, it is suggested that they reflect two distinct processes in the light-evoked potential of the photoreceptor cells.List of the more important symbols
V
s
Potential of fixed electrode at the surface of retina relative to grounded electrode
-
V
p
Potential of moveable electrode relative to ground
-
V
D
V
s
- V
p
-
V
m
Maximum value of V
s
produced by saturating light intensities
-
I
o
Stimulus required to evoke a response of half-maximal amplitude
-
g
K
Membrane potassium conductance
-
g
Na
Membrane sodium conductance
-
E
K
Nernst potential for potassium
-
E
Na
Nernst potential for sodium
-
G
Coefficient connecting light intensity and light-induced change of conductance
-
t
R
Time, measured from the stimulus onset, for the response to reach 50% of peak amplitude
-
t
F
Time, measured from the time to peak, for the response to fall to 50% of its maximal value 相似文献
18.
The structural determinants of mibefradil inhibition were analyzed using wild-type and inactivation-modified CaV1.2 (α1C) and CaV2.3 (α1E) channels. Mibefradil inhibition of peak Ba2+ currents was dose- and voltage-dependent. An increase of holding potentials from −80 to −100 mV significantly shifted dose-response
curves toward higher mibefradil concentrations, namely from a concentration of 108 ± 21 μm (n= 7) to 288 ± 17 μm (n= 3) for inhibition of half of the Cav1.2 currents (IC
50) and from IC
50= 8 ± 2 μm (n= 9) to 33 ± 7 μm (n= 4) for CaV2.3 currents. In the presence of mibefradil, CaV1.2 and CaV2.3 experienced significant use-dependent inhibition (0.1 to 1 Hz) and slower recovery from inactivation suggesting mibefradil
could promote transition(s) to an absorbing inactivated state. In order to investigate the relationship between inactivation
and drug sensitivity, mibefradil inhibition was studied in inactivation-altered CaV1.2 and CaV2.3 mutants. Mibefradil significantly delayed the onset of channel recovery from inactivation in CEEE (Repeat I + part of
the I–II linker from CaV1.2 in the CaV2.3 host channel), in EC(AID)EEE (part of the I–II linker from CaV1.2 in the CaV2.3 host channel) as well as in CaV1.2 E462R, and CaV2.3 R378E (point mutation in the β-subunit binding motif) channels. Mibefradil inhibited the faster inactivating chimera EC(IS1-6)EEE with an IC
50= 7 ± 1 μm (n= 3), whereas the slower inactivating chimeras EC(AID)EEE and CEEE were, respectively, inhibited with IC
50= 41 ± 5 μm (n= 4) and IC
50= 68 ± 9 μm (n= 5). Dose-response curves were superimposable for the faster EC(IS1-6)EEE and CaV2.3, whereas intermediate-inactivating channel kinetics (CEEE, CaV1.2 E462R, and CaV1.2 E462K) were inhibited by similar concentrations of mibefradil with IC
50≈ 55–75 μm. The slower CaV1.2 wild-type and CaV1.2 Q473K channels responded to higher doses of mibefradil with IC
50≈ 100–120 μm. Mibefradil was also found to significantly speed up the inactivation kinetics of slower channels (CaV1.2, CEEE) with little effect on the inactivation kinetics of faster-inactivating channels (CaV2.3). A open-channel block model for mibefradil interaction with high-voltage-activated Ca2+ channels is discussed and shown to qualitatively account for our observations. Hence, our data agree reasonably well with
a ``receptor guarded mechanism' where fast inactivation kinetics efficiently trap mibefradil into the channel.
Received: 14 March 2001/Revised: 25 June 2001 相似文献
19.
QIANG ZHAO DE-LING KONG BING-JUN HE YAN-QIANG LIU XIAN-LIN FAN AN-XI LIU 《Insect Science》2007,14(2):107-115
Pertussis toxin (FIX) inhibits the activation of the α-subunit of the inhibitory heterotrimeric G-proteins (Cαi/o) and modulates voltage-gated sodium channels, which may be one of the primary targets of pyrethroids. To investigate the potential mechanisms of agricultural pests resistance to pyrethroid insecticides, we examined the modulations by PTX on sodium channels in the central neurons of the 3rd-4th instar larvae of cyhalothrin-resistant (Cy-R) and cyhaiothrin-susceptible (Cy-S) Helicoverpa armigera by the whole-cell patch-clamp technique. The isolated neurons were cultured for 12-16 h in an improved L15 insect culture medium with or without PTX (400 ng/mL). The results showed that both the Cy-R and Cy-S sodium channels exhibited fast kinetics and tetrodotoxin (TTX) sensitivity. The Cy-R sodium channels exhibited not only altered gating properties, including a 8.88-mV right shift in voltage-dependent activation (V0.5act) and a 6.54-mV right shift in voltage-dependent inactivation (V0.5inact), but also a reduced peak in sodium channel density (Ⅰdensity) (55.2% of that in Cy-S neurons). Cy-R sodium channels also showed low excitability, as evidenced by right shift of activation potential (Ⅴacti) by 5-10 mV and peak potential (Ⅴpcak) by 20 mV. FIX exerted significant effects on Cy-S sodium channels, reducing sodium channel density by 70.04%, right shifting V0.5act by 14.41 mV and V0.5inact by 9. 38 mV. It did not cause any significant changes of the parameters mentioned above in the Cy-R sodium channels. The activation time (Tpeak) from latency to peak at peak voltage and the fast inactivation time constant (τinact) in both Cy-S and Cy-R neurons were not affected. The results suggest that cotton bollworm resistant to pyrethroid insecticides involves not only mutations and allosteric alterations of voltage-gated sodium channels, but also might implicate perturbation of PTX-sensitive Gαi/o-COupled signaling Wansduction pathways. 相似文献
20.
Transient potassium currents distinctively affect firing properties, particularly in regulating the latency before repetitive
firing. Pyramidal cells of the dorsal cochlear nucleus (DCN) have two transient potassium currents, I
Kif and I
Kis, fast and slowly inactivating, respectively, and they exhibit firing patterns with dramatically variable latencies. They
show immediate repetitive firing, or only after a long latency with or without a leading spike, the so-called pauser and buildup
patterns. We consider a conductance-based, ten-variable, single-compartment model for the DCN pyramidal cells (Kanold and
Manis 2001). We develop and analyze a reduced three-variable integrate-and-fire model (KM-LIF) which captures the qualitative
firing features. We apply dynamical systems methods to explain the underlying biophysical and mathematical mechanisms for
the firing behaviors, including the characteristic firing patterns, the latency phase, the onset of repetitive firing, and
some discontinuities in the timing of latency duration (e.i. first spike latency and first inter spike interval). Moreover,
we obtain new insights associated with the leading spike by phase plane analysis. We further demonstrate the effects of possible
heterogeneity of I
Kis. The latency before repetitive firing can be controlled to cover a large range by tuning of the relative amounts of I
Kif and I
Kis. Finally, we find for the full system robust bistability when enough I
Kis is present. 相似文献