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The Journal of Neuroscience, October 1, 1999, 19(19):8163-8171
Arachidonic Acid Reciprocally Alters the Availability of
Transient and Sustained Dendritic K+ Channels in
Hippocampal CA1 Pyramidal Neurons
Costa M.
Colbert and
Enhui
Pan
Department of Biology and Biochemistry, University of Houston,
Houston, Texas 77204-5513
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ABSTRACT |
The dendrites of hippocampal CA1 pyramidal cell dendrites express a
high density of transient A-type K+ channels, which
play a critical role in the back-propagation of action potentials and
in the determination of dendritic excitability. Recently, arachidonic
acid and its nonmetabolizable analogue 5,8,11,14-eicosatetraynoic acid
(ETYA) were shown to block transient K+
channels in the somata of these cells (Keros and McBain, 1997 ), but to
have little effect on the somatic action potential. In the present
study we have investigated the effects of arachidonic acid and ETYA on
the gating of channels and the excitability of the apical dendrites of
CA1 pyramidal neurons. We found not only a block of transient
K+ channels, but also an enhancement of sustained
outward currents. The sustained currents consisted of at least two
distinct channel types. The larger conductance channel (>50 pS) was
identified as a K+ channel. Arachidonic acid greatly
enhanced the amplitude of back-propagating dendritic action potentials
(>200 µm from the soma) but did not result in sustained
depolarizations of the dendrites similar to those seen with
4-aminopyridine (4-AP) application. In fact, arachidonic acid reduced
dendritic excitability when applied after 4-AP. Thus, arachidonic acid
appears to cause a shift of available channels from the fast, transient
type to the slower, sustained types. The net effect appears to be an
enhancement of dendritic action potential amplitude that occurs without
compromising the electrical stability of the dendrites.
Key words:
arachidonic acid; dendrite; single channel
recording; potassium channel; pyramidal neuron; electrophysiology; rat
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INTRODUCTION |
Back-propagating dendritic action
potentials provide a rapid means for pyramidal neurons to signal their
firing state throughout their extensive dendritic arbors (Jaffe et al.,
1992; Stuart et al., 1997; Magee et al., 1998). By providing both a
strong postsynaptic depolarization and Ca2+ influx,
the back-propagating action potential may be critical in signaling the
induction of associative processes such as long-term potentiation
(Magee and Johnston, 1997; Markram et al., 1997). The amplitude of the
dendritic back-propagating action potential, however, is not
all-or-none, but decreases steadily as it travels away from the soma
(Turner et al., 1991; Spruston et al., 1995; Svoboda et al., 1997;
Buzsáki and Kandel, 1998). How far the action potential travels
in the dendrites depends strongly on the previous level of dendritic
depolarization (Tsubokawa and Ross, 1996; Hoffman et al., 1997; Magee
et al., 1998), the postsynaptic firing rate (Callaway and Ross, 1995;
Spruston et al., 1995), and the state of various neuromodulatory
systems (Tsubokawa and Ross, 1997; Hoffman and Johnston, 1999).
Recent work has identified the ionic mechanisms responsible for the
decremental nature of the back-propagating dendritic action potential
in CA1 pyramidal neurons. Transient A-type K+
channels in the apical dendrites, putatively identified as Kv4.2 (Sheng
et al., 1992; Maletic-Savatic et al., 1995) (for review, see Hoffman
and Johnston, 1998), steadily increase in density with distance from
the soma (Hoffman et al., 1997). As the back-propagating action
potential travels through the dendrites, it encounters increasing
outward current that eventually limits propagation. Thus, modulation of
transient K+ channel properties impacts
back-propagation (Hoffman et al., 1997). Activation of either protein
kinase A (PKA) or protein kinase C (PKC), for example, alters the
voltage dependence of activation of the transient K+
channels (Hoffman and Johnston, 1998) and thereby alters
back-propagation.
In addition to phosphorylation by kinases, Kv4.2 channels (Villarroel
and Schwarz, 1996) and transient K+ channels in CA1
somata (Keros and McBain, 1997) are inhibited by arachidonic acid and
its nonmetabolizable analog 5,8,11,14-eicosatetraynoic acid
(ETYA). Keros and McBain (1997) demonstrated a dose-dependent block of transient K+ current associated with an
increase in the rate of inactivation in somatic macropatches. However,
under normal conditions, they found an absence of effect on the somatic
action potential. Given the much higher density of transient
K+ channels in the apical dendrites, we hypothesized
that application of arachidonic acid would have a much greater effect
on the dendritic action potential. Indeed, we observed a profound
increase in action potential amplitude in the presence of arachidonic
acid. However, this increase in amplitude was not accompanied by
sustained Ca2+ spikes that are normally associated
with the block of K+ channels by 4-aminopyridine
(4-AP; Hoffman et al., 1997, their Fig. 3). Observing the
effects of arachidonic acid on K+ currents in
dendritic cell-attached patches, we found not only inhibition of the
rapidly activating transient current, but an enhancement of more slowly
activating sustained currents. Thus, arachidonic acid may dynamically
regulate the balance of dendritic K+ currents,
allowing a larger back-propagating action potential while maintaining
electrical stability of the dendrites.
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MATERIALS AND METHODS |
Preparation and solutions. The present study used
120-180 gm male Sprague Dawley rats. Animals were anesthetized with a
lethal dose of a combination of ketamine and xylazine. Once deeply
anesthetized, they were perfused through the heart with cold modified
artificial CSF containing (in mM), 110 sucrose, 60 NaCl, 3.0 KCl, 1.25 NaH2PO4, 28 NaHCO3, 0.5 CaCl2, 7.0 MgCl2, and 5 dextrose. After removal of the brain,
400-µm-thick slices were cut using a Vibratome (Lancer), incubated
submerged in a holding chamber for 30 min at 32°C, and stored
submerged at room temperature.
During the slicing procedure, the slices were maintained in the same
ACSF as used for the perfusion. The external recording solution
contained (in mM) 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 25 NaHCO3,
2.0 CaCl2, 1.0 MgCl2, and 25 dextrose. Slices were maintained in a submerged holding chamber in the
normal external recording solution. All external solutions were bubbled
continuously with 95% O2 and 5% CO2. The
internal pipette solution used for whole-cell recordings contained (in
mM), 140 KGluconate, 10 HEPES, 1 EGTA, 4.0 NaCl, 4.0 Mg2ATP, 0.3 Mg2GTP, and 14 phosphocreatine. pH
was adjusted to 7.25 with KOH. For recording K+
currents in the cell-attached configuration, the pipette contained (in
mM), 130 NaCl, 10 HEPES, 2 CaCl2, 1 MgCl2, 2.5 KCl, and 1 µM tetrodotoxin
(TTX). pH was adjusted to 7.4 with NaOH. Where indicated, 10 mM tetraethylammonium (TEA) and/or 1 mM 4-AP
was included, or TTX was excluded from the pipette solution. For
recording K+ currents in the inside-out
configuration, the pipette solution contained (in mM), 76 NaCl, 10 HEPES, 2 CaCl2, 1 MgCl2,
37.5 KCl, and 1 µM TTX. The bath solution for inside-out
recordings eliminated CaCl, added 10 mM EGTA, and replaced
NaCl with 134 mM KCl. Synaptic receptor antagonists (see
below) and TTX were also included to limit activity in the slice.
Inside-out patches were made in normal extracellular solution. After
the seal was made, the bath solution was switched to the
high-K+, low Ca2+ solution, and
the patch was ripped off the cell.
Arachidonic acid (AA; sodium salt) and ETYA (free acid) were obtained
from Sigma (St. Louis, MO). AA was dissolved in water or ethanol. ETYA
was dissolved in dimethylsulfoxide (DMSO). Stock solutions of ~10
mM were made and divided into aliquots, which were kept in
a  80°C freezer. Both substances were extremely labile. Once this
fact became apparent, stock solutions were thawed, brought to final
concentrations, vortexed, and added to the reservoir during acquisition
of control data. When added to the cell-attached pipettes, freshly
thawed drug was added to the pipette solution just before filling the
pipette. This protocol improved the consistency of the effects
dramatically. Final concentration of DMSO was <0.5%. DMSO was washed
into the bath without effects on currents in the cell-attached patch
(n = 2). Bovine serum albumin (BSA; 1 mg/ml; Sigma),
which binds fatty acids, was added to the bath to aid recovery.
Recording techniques. Recordings were made from
somata and dendrites of hippocampal CA1 pyramidal neurons. Neurons were
visualized using infrared illuminated, differential interference
contrast (DIC) optics (Olympus Optical, Tokyo, Japan) according to
standard techniques (Stuart et al., 1993). Whole-cell patch recordings were made using microelectrode amplifiers (BVC-700; Dagan Instruments) in bridge mode. Cell-attached patch recordings were made using a
patch-clamp amplifier with a capacitive headstage (Axopatch 200; Axon
Instruments, Foster City, CA). Pipettes (3-5 M for whole-cell;
7-12 M for cell-attached) were made from borosilicate glass (Warner
Glass) and pulled using a P-87 Flaming-Brown pipette puller (Sutter
Instruments) and coated with Sylgard (Dow Corning). Most cell-attached
patch recordings were made at room temperature (~25°C). Whole-cell
recordings were made at 30-32°C. Whole-cell series resistance was
6-20 M for somatic recordings and 15-40 M for dendritic
recordings. All cells used had initial resting membrane potentials
negative to 60 mV, and typically were in the range of 65 to 70
mV. Whole-cell recordings were low-pass filtered at 3 kHz (6 dB/octave)
and digitized at 10 kHz. Cell-attached patch recordings were filtered
at 2 kHz (8 pole Bessel filter) and sampled at 10 kHz. Data were
digitized at 16 bit resolution (ITC-18; Instrutech) and stored by
computer for offline analysis (Next Computer). Nonlinear curve fits and
statistical tests were made using Mathematica (Wolfram). Significance
was determined by t test with p < 0.05 considered significant. Data are reported as mean ± SEM.
K+ currents were recorded in the cell-attached and
inside-out configurations. Typically, patches were held at 30 mV
negative to the resting potential of the cell to remove inactivation of transient channels. Potentials reported are the transmembrane potentials. Effects of the drugs were observed using command potentials of +20-50 mV. Ensemble averages were calculated from 30-50 sweeps unless otherwise noted. Leak currents were determined by scaling smaller (20 mV) steps digitally offline. Leak steps were interleaved with test steps continuously throughout each experiment to monitor any
changes in leak currents. Membrane potentials were determined when
possible by rupturing the patch after data collection and were in the
range of 65 to 70 mV. As an additional test of depolarization of
the cell during cell-attached recordings, the patch was held hyperpolarized at 50 mV and stepped to the same command potentials. If an increase in transient current was noted, the cell was assumed to
have depolarized, and the patch was excluded from further analysis. Patches were also excluded if capacitive currents caused by cell firing
were detected. Reported transient K+ current
amplitudes were measured at the peak of the current waveform current.
Sustained current amplitudes were measured as the mean value of current
in the last 10 msec of the depolaring voltage command, ~150 msec.
Antidromic action potentials were stimulated by constant current pulses
(Neurolog; Digitimer Ltd.; 70-500 µA) through monopolar tungsten
electrodes (AM Systems) placed in the alveus. Positioning of the
stimulating electrodes and the intensity of stimulation minimized
synaptic activation. To limit any synaptic activation during antidromic
stimulation, the glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 µM) and
2-amino-5-phosphono-valeric acid (AP-5; 50 µM) and the
GABAA receptor antagonist bicuculline methiodide (10 µM) were routinely added to the extracellular solution. Antagonists were obtained from Sigma.
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RESULTS |
ETYA increases the amplitude of the back-propagating dendritic
action potential
Rapidly inactivating K+ channels play a
critical role in shaping back-propagating dendritic action potentials
in CA1 pyramidal neurons (Hoffman et al., 1997). Therefore, we
hypothesized that blockade of the transient K+
channels by arachidonic acid should increase the amplitude of back-propagating action potentials. Interpretation of arachidonic acid
actions is complicated by the fact that it is rapidly metabolized to
form intermediates that are important second-messengers in a variety of
processes. Thus, to aid the interpretation of the results by reducing
the range of metabolites produced, we used an analogue of arachidonic
acid, ETYA, that is not a substrate for the major metabolic pathways of
arachidonic acid. ETYA has been demonstrated previously to block
transient K+ channels with an efficacy and potency
similar to arachidonic acid (Villarroel and Schwarz, 1996; Keros and
McBain, 1997; Dryer et al., 1998).
To observe the effects of ETYA on the back-propagating action
potential, we made whole-cell recordings from the apical dendrites of
CA1 pyramidal cells 200-225 µm from the soma. Antidromic action potentials were evoked (0.1 Hz) by a stimulating electrode placed in
the alveus. After recording 20-30 dendritic action potentials, the
bath solution was switched to a solution containing ETYA (40 µM). The amplitude of the back-propagating action
potential increased to 142 ± 9% of its control value
(n = 5). Figure 1 shows
an example of the effect of ETYA and its reversibility with washout.
Figure 2A shows
additional examples of back-propagating dendritic action potentials
before and after application of ETYA. In two cases, the
back-propagating action potentials reached ~100 mV, comparable to a
somatic action potential. Application of ETYA, however, did not
simultaneously increase the maximum rate of rise of the dendritic action potential (4 ± 3%; n = 5; Fig.
1B). This finding suggests that the increase in
dendritic action potential amplitude is caused by a decrease in
K+ conductance rather than an increase in
Na+ conductance (cf. Colbert et al., 1997). Figure
2C summarizes the results of bath application of ETYA.
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Figure 1.
Bath application of ETYA reversibly increases the
amplitude of the back-propagating action potential. Whole-cell
recording from the apical dendrite 200 µm from the soma. Action
potentials were evoked by a stimulating electrode in the alveus.
A, a, Control dendritic action potential. In the
remaining panels, this waveform is shown as a dotted line
for comparison. b, ETYA (40 µM) increases the
amplitude of the dendritic action potential. c, Dendritic
action potential before washout begins. d, After washout the
dendritic action potential has similar amplitude to the control action
potential. Bovine serum albumin (1 mg/ml) was added to the bath to aid
washout. B, Time course of bath application of ETYA
experiment. Graph plots the amplitude of the dendritic action potential
during the experiment. Letters above the plot identify
the points corresponding to the waveforms in A. After the
action potential increased, the electrode series resistance began to
increase. The electrode was cleared (asterisk), and a new
baseline was achieved before washout began. Membrane potential was held
at 65 mV throughout the experiment.
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Figure 2.
Bath application of ETYA increases dendritic
action potentials but not maximum rate of rise. A, Results
from two cells showing that ETYA (40 µM) can increase the
amplitude of the back-propagating dendritic action potential to nearly
that of a somatic action potential (90-100 mV). Note, however, that
there was no Ca2+ spike triggered by these large
dendritic spikes, as seen when dendritic action potential amplitude is
increased by 4-AP (compare Fig. 10) B, Despite the increase
in amplitude, the maximum rate of rise of the action potential (dV/dt)
does not increase. Rates of rise were computed by subtraction of
successive data samples. C, Summary of bath application of
ETYA (n = 5 cells). Significant changes are marked with
an asterisk.
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Bath application of arachidonic acid (30 µM) or
phospholipase (PLA2; 2 U/ml), which releases
arachidonic acid from cell membranes, also increased the amplitude of
the back-propagating dendritic spike. Arachidonic acid increased the
magnitude of the spike to 137 ± 18% (n = 3) of
control. PLA2 increased the magnitude of the spike to
153 ± 27% (n = 2) of its control value.
Arachidonic acid and ETYA alter dendritic outward currents
Keros and McBain (1997) characterized the effects of arachidonic
acid and ETYA on transient channels in macropatches from CA1 somata.
Our intent here was not to repeat this entire characterization in the
dendrites, but to verify that arachidonic acid and ETYA blocked
transient K+ channels in the apical dendrites (i.e.,
>200 µm from the soma). We chose to use cell-attached patches in
order to preserve the normal cytoplasmic environment of the channels,
avoiding such complicating factors as cysteine oxidation (noted by
Keros and McBain, 1997). The major disadvantage of cell-attached
patches is that bath-applied drug must penetrate the cell within the
slice and reach channels that are pulled up into the recording pipette during the lifetime of the patch.
Initially, we tested the block of transient K+
channels by comparing K+ currents across two groups
of cell-attached patches. The test group included ETYA (40 µM) in the pipette solution. K+
currents were evoked by voltage steps from a holding potential of 90
mV to a command potential of +30 mV. To normalize for differences in
the size of the patches, we calculated the ratio of the peak transient
current amplitude to the sustained current amplitude for each patch. If
ETYA blocks the transient current, then this ratio should be decreased.
The ratio of the peak transient current to sustained current in the
control group was 4.7 ± 1.0 (n = 8). Two small
control patches were excluded because the sustained current amplitude
was essentially zero, yielding very high ratios. In contrast, the ratio
of the peak transient current to the sustained current for the ETYA
group was (1.7 ± 0.5; n = 7). Thus, the ratio for
the ETYA group was significantly smaller than that of the control
group, supporting the hypothesis that the transient current was reduced
by ETYA. However, the group averages suggested that ETYA might have had
an additional effect. Although not quite reaching our definition of
significance, the sustained current (7.1 ± 1.6 pA;
n = 8) was greater than the sustained current in the
control group (3.6 ± 1.0 pA; n = 10;
p < 0.06). Thus, we reasoned that the ratio of
amplitudes might be decreased not only by the blockade of transient
current, but also by an enhancement of the sustained current.
To investigate the actions of ETYA further, we bath-applied ETYA to
provide within-patch controls. After data were collected in the normal
extracellular solution, we switched to extracellular solution
containing ETYA (30 µM). In the first set of patches we
observed the effects of ETYA on pharmacologically isolated transient
current. In addition to TTX, 4-AP (1 mM) was included in
the pipette solution to block slower transient currents (i.e., D-current) and TEA (10 mM) was included to block delayed
rectifier-type currents. ETYA significantly reduced the amplitude of
the isolated transient current to 46.2 ± 18.4%
(n = 5) of control. The time constant of inactivation,
as fit by a single exponential, also decreased significantly to 61 ± 11% (n = 5) of control from an initial value of
13.4 ± 3.0 msec. Figure 3 is an
example of such an experiment.
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Figure 3.
Bath application of ETYA (40 µM)
decreases the amplitude of fast, transient A-type K+
channel currents in cell-attached dendritic patches. Cell-attached
patch from apical dendrite ~200 µm from the soma. Sustained and
slowly inactivating K+ currents were blocked with
4-AP (1 mM) and TEA (10 mM) in the patch
pipette solution. Transient K+ currents were evoked
by voltage steps from 90 to +30 mV. A, Kinetics during
progressive block by ETYA. Ensemble averages of 10 sweeps are shown
superimposed. Solid lines are exponential fits of the data.
Time constants given are single exponential time constants. Data were
well-fit by single exponentials. The time constant decreases with block
of the channels. B, Time course of bath application
experiment. The graph plots the peak amplitude of the transient current
throughout the experiment. ETYA was switched off as soon as an effect
was detected to aid washout. Numbers above the plot
correspond to the ensemble averages and time constants shown in
A. C, Summary of ETYA effect on transient current
(n = 5 cells).
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In a second set of patches we looked for other effects of ETYA by
excluding K+ channel blockers from the patch pipette
(Fig. 4). After bath-applying ETYA, there
was an initial increase in the sustained outward current. After a few
minutes, the transient current decreased while the sustained current
remained increased. The increase in sustained current was seen in three
of the five patches observed. In the remaining two patches there was
essentially no change in the sustained current. Figure
4B summarizes the experiment. The transient current decreased significantly to 70.4 ± 10.7% (n = 5)
of control, whereas the sustained current increased significantly to
153.3 ± 23.5% (n = 5) of control.
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Figure 4.
Bath application of ETYA (40 µM)
enhances sustained current while decreasing transient current.
A, Top panel, K+ currents were
evoked by voltage steps from 90 to +30 mV. No K+
channel blockers were included in the patch pipette. Top
panel, Waveform is ensemble average of 30 sweeps in control
solution, showing transient and sustained currents. Middle
panel, Solid waveform is ensemble average of 15 sweeps beginning 8 min after start of bath application of ETYA, showing an increase in the
sustained current and a small decrease in the transient current.
Bottom panel, Solid waveform is ensemble average of 15 sweeps beginning 24 min after the start of ETYA. The 8 min waveform is
shown as a dotted line for comparison. There is no further
increase of the sustained current, but the transient current continues
to decrease in amplitude. B, Summary of the ETYA effect on
transient and sustained outward currents after 20-30 min
exposure.
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To verify that arachidonic acid has the same effect as ETYA on
dendritic K+ channels, we repeated the bath
application experiment using 30 µM arachidonic acid (Fig.
5A). Arachidonic acid
significantly decreased the amplitude of the transient current to
52.1 ± 15.7% (n = 7) of its control value. The
inactivation time constant fit by a single exponential significantly
decreased to 56.9 ± 15.5% of its control value of 13.6 ± 2.1 (n = 4) msec. As in the ETYA experiment, the
sustained current increased in four of seven of the patches. The
increase in the sustained current was 163.7 ± 41%
(n = 6) of its control value. The arachidonic acid
experiment is summarized in Figure 5B. Pooling the data from
the two sets of experiments, bath application of fatty acids increased
the sustained current to 158.9 ± 23.7% of the control value
(n = 12; p < 0.016; one-tailed
test).
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Figure 5.
Bath application of arachidonic acid (30 µM) enhances sustained current while decreasing transient
current. A, Top panel, Ensemble averages of 12 sweeps in control conditions for steps from 90 mV to command
potentials from 30 to +50 mV. Bottom panel, Ensemble
averages of 15 sweeps after application of arachidonic acid.
B, Summary of experiment. Arachidonic acid decreased the
amplitude of the transient current and the inactivation time constant
( ), while increasing the amplitude of the sustained current.
C, Activation curves for the transient currents before
(open squares) and after (filled dots)
application of arachidonic acid. Block of the transient current was not
associated with a significant shift in the activation curve. Error bars
were approximately the size of the symbols. Lines represent
least-squares fit to Boltzmann (see Materials and
Methods).
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Keros and McBain (1997) suggested that the block of the somatic
transient K+ channels by arachidonic acid was not
caused by a shift in the activation curve. This differs from modulation
of the dendritic transient K+ channels by kinases
(Hoffman and Johnston, 1998), which appear to act by shifting the
activation curve. Thus, we obtained activation curves for the transient
K+ current before and during the arachidonic acid
experiment just described. Assuming a K+ reversal
potential of approximately 95 mV, the conductance at +40 mV was
93 ± 0.5% (n = 6) of the value at +50 mV, the
greatest depolarization we used to construct the activation plots.
Although there was an ~50% block of the transient current (as
described above), there was no shift in the normalized activation
curves (Fig. 5C). Least-squares fits of Boltzmann functions
yielded half-maximal activations at 3.9 and 1.7 mV and slopes of
k = 15.6 and k = 15.4 before and after
application of arachidonic acid, respectively.
Examining individual current traces before and after the bath
application of arachidonic acid and ETYA yielded additional information
about the nature of the sustained currents. In most patches, individual
openings were not well resolved. However, in some patches only a few
channels contributed to the sustained ensemble current. These patches
revealed more than one source of additional current. Figure
6 shows the first. The top panel of
Figure 6A shows ensemble averages before and after
application of ETYA. The bottom panels show examples of single sweeps
in which single channel openings can be seen. Figure
6B shows the individual data samples superimposed.
The data points begin 80 msec after the voltage command to allow the
transient current to decay (i.e., Fig. 6A between the
arrows). Favored levels can be seen as a high density of
samples. Application of ETYA resulted in a shift of the favored levels
to higher current. An all-points histogram made from these data (Fig.
6C) suggests that the favored current levels are multiples
of 1.9 pA or ~15 pS. Application of ETYA resulted in a shift in the
favored levels to another multiple of 1.9 pA, consistent with either an
increased probability of opening of channels in the patch or the
recruitment of an additional channel of similar unitary conductance. A
similar shift in discrete current levels was noted in two additional
patches.
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Figure 6.
Enhancement of sustained current by a
small conductance channel. A, Top panel,
K+ currents in a cell-attached patch ~200 µm
from the soma evoked by a step from 87 to +17 mV. Ensemble averages
of 25 sweeps before and after application of ETYA showing enhancement
of sustained current. Middle and Bottom panels,
Individual sweeps show clear openings and closings of sustained
channels. B, Plotting the sample points beginning 80 msec
after the step depolarization (A, between the arrows)
demonstrates two favored levels of current for the sustained channels,
and a shift in the favored level after ETYA application. C,
Plotting these data as all-points histograms indicates clear peaks at
multiples of 1.9 pA (~15 pS). After ETYA there is a shift in the
favored level, but the same peaks are maintained. Thus, the additional
conductance may be caused by increased opening of the same channels or
activation of additional channels of similar conductance.
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The second source of outward current that appeared after the
application of ETYA or arachidonic acid was associated with
large-conductance channel openings. Figure
7 shows an example of such a channel. Figure 7A shows 15 consecutive superimposed sweeps in the
control condition and their resulting ensemble average. Figure
7B shows 15 consecutive sweeps from the same patch after the
application of arachidonic acid and the resulting ensemble average. A
new favored current level appears, increasing the sustained current in
the ensemble average. Figure 7C shows individual traces,
suggesting that these increases in current are caused by openings of a
large-conductance channel. From the linear portion of the IV plot, the
unitary conductance of this channel was 55 pS.
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Figure 7.
Enhancement of sustained current by a large
conductance channel. A, K+ currents in a
cell-attached patch ~200 µm from the soma evoked by a step from
90 to +30 mV. A, Control, 10 superimposed
consecutive sweeps and their ensemble average showing transient and
sustained currents. B, 10 superimposed consecutive sweeps
and their ensemble average after bath application of arachidonic acid.
Note that transient currents decrease and a new favored level appears,
enhancing the sustained current in the ensemble average. C,
Individual sweeps from B show the favored level results from
the opening of a larger conductance channel (~55 pS).
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Finally, to determine whether the fatty acid-activated currents were
carried by K+ ions, we applied ETYA to inside-out
patches. We used a pipette solution of relatively high
K+ to limit rectification of the channels, and thus,
allow us to determine the reversal potential. Figure
8 shows an example of such a recording.
The patch was held at 30 mV and stepped to a command potential of +40
mV once each 3 sec. After application of ETYA, a large-conductance
outward current appeared. From the IV plot, (Figure
8B,C) the conductance was
determined to be 89 pS, and the reversal potential was 39 mV. This
reversal potential corresponds closely to the calculated
K+ equilibrium potential of 35 mV. In some
patches, ETYA activated a smaller conductance channel with a unitary
conductance of 16 pS. This channel is probably identical to the smaller
conductance channel seen in the cell-attached recordings. In each case,
the currents reversed at approximately 40 mV, suggesting that they are carried by K+ channels.
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Figure 8.
Reversal potential of large-conductance channel
activated by ETYA. Currents in an inside-out patch from ~150 µm
from soma. Pipette solution included high K+ to
decrease rectification and allow an estimate of the reversal potential.
A, The patch was held at 30 mV to inactivate transient
currents and stepped to a command potential of +30 mV. Waveforms are 15 consecutive individual sweeps before (control) and
after (ETYA) application of ETYA (40 µM) to
the bath. Data are not leak-subtracted. B, Representative
traces at various potentials to show single-channel openings. Patch was
held at 90 mV and stepped to potentials from 60 to +60 mV as
indicated. Waveforms begin ~50 msec after the step. C,
I-V plot constructed from unitary currents as in
B. From the best fit line, the slope yields a conductance of
89 pS, and the current reverses near 40, near the calculated
equilibrium potential for K+.
|
|
Redistribution of outward current increases action potential
amplitude while maintaining membrane stability
In previous studies, the amplitude of the dendritic
back-propagating action potential was increased by blocking transient K+ current with 4-AP (Colbert et al., 1997; Hoffman
et al., 1997). These large action potentials were invariably
accompanied by sustained Ca2+-dependent plateau
potentials in the dendrites and eventually by an inability of the cell
to repolarize. In contrast, application of ETYA and arachidonic acid
greatly increased the amplitude of the back-propagating spike (Figs. 1,
2), but did not induce sustained depolarizations and bursts. We
hypothesized that the enhancement of the sustained current by
arachidonic acid and ETYA might limit these bursts. To test this idea,
we observed the effect of arachidonic acid on bursting and on sustained
depolarizations induced by previous application of 4-AP (Fig.
9; n = 5). Whole-cell
dendritic recordings were made at >200 µm from the soma to monitor
back-propagating action potentials. 4-AP (4 mM) added to
the bath increased the amplitude of the back-propagating action
potential. Once the effect of 4-AP began, sustained depolarizations of
the dendritic membrane followed nearly every back-propagating action
potential. In all but one cell, subsequent application of arachidonic
acid (30 µM) shortened the bursts and decreased the
probability of evoking bursts. In the example shown (Fig.
9C), bursts were eventually blocked completely. The
amplitude of the back-propagating action potential remained greatly
increased as expected from the block of transient K+
current by both 4-AP and arachidonic acid.
View larger version (9K):
[in this window]
[in a new window]
|
Figure 9.
Arachidonic acid decreases the sustained
depolarizations and bursts resulting from K+ channel
blockade by 4-AP. Whole-cell recording from apical dendrite ~200 µm
from the soma. Back-propagating action potentials were evoked by a
stimulating electrode in the alveus. A, Antidromic
stimulation evokes a back-propagating action potential in the
dendrites. B, Bath application of 4-AP (4 mM)
increases the amplitude of the dendritic action potential, but results
in large, sustained Ca+ spikes. C,
Approximately 15 min after application of arachidonic acid (30 µM), the sustained depolarizations were completely
blocked, leaving a single back-propagating action potential nearly
twice the amplitude it had in the initial control condition.
|
|
To further investigate the relationship of transient and sustained
currents to dendritic membrane stability, we observed the effects of
ETYA and arachidonic acid during a partial block of the sustained
currents with TEA (4-10 mM). TEA was either included in
the whole-cell patch pipette (n = 4) or bath-applied
(n = 3). TEA alone did not cause bursting or sustained
depolarizations when applied alone (data not shown). Figure
10 shows an example of serial bath
application of arachidonic acid and TEA. Bath application of
arachidonic acid (30 µM) decreased the threshold for
action potential initiation in response to a dendritic current
injection (Fig. 10A, top and
middle panels), but did not result in sustained depolarizations. Subsequently adding TEA (4 mM) to the bath
quickly resulted in a sustained depolarizing plateau potential. These results suggest that the sustained current is important in maintaining membrane stability when the transient current is decreased either by
modulation or by activity-dependent inactivation. Furthermore, it
suggests that the decrease in bursting seen in the 4-AP and arachidonic
acid experiment above is not likely caused by blockade of
Ca2+ channels by arachidonic acid.
View larger version (15K):
[in this window]
[in a new window]
|
Figure 10.
Block of sustained currents produces sustained
depolarizations. Whole-cell recording from an apical dendrite ~200
µm from the soma. Current was injected through the dendritic
recording electrode to depolarize the dendrite. A, In the
control condition the current injection was below the threshold for
initiating action potentials. B, Bath application of
arachidonic acid lowered the threshold for initiating action
potentials. Note that there was some tendency for spikes to cluster,
but no sustained bursts. C, Subsequent addition of TEA (4 mM) to the bath to block sustained currents allowed
sustained depolarizations to occur. Thus, sustained currents contribute
to membrane stability when transient currents are reduced. These data
also demonstrate that Ca2+ currents, which may be
reduced by arachidonic acid, are still sufficient under these
conditions to produce a sustained depolarization.
|
|
| |
DISCUSSION |
Decremental back-propagating action potentials have been
extensively studied in the apical dendrites of pyramidal neurons in
both hippocampus and neocortex (Turner et al., 1991; Stuart and
Sakmann, 1994; Spruston et al., 1995; Buzsáki et al., 1996; Svoboda et al., 1997). Although the full range of their function is not
fully understood, a potential role as a rapid, long-range intracellular
signal for synaptic plasticity has been demonstrated (Magee and
Johnston, 1997). Perhaps the most intriguing aspect of the
back-propagating action potential as an intracellular signal is that it
is highly conditional. That is, both the history of activity (Callaway
and Ross, 1995; Spruston et al., 1995; Colbert et al., 1997; Hoffman et
al., 1997; Magee and Johnston, 1997) and the state of various
neuromodulatory systems (Tsubokawa and Ross, 1997; Hoffman and
Johnston, 1999) greatly determine the efficiency of back-propagation.
Thus, the back-propagating action potential provides a critical
regulatory substrate for the control of synaptic plasticity.
Recent work has identified the transient A-type K+
channels, primarily of the Kv4.2 subtype (Sheng et al., 1992;
Maletic-Savatic et al., 1995; Serôdio et al., 1996), as the major
determinant of dendritic action potential amplitude in CA1 pyramidal
neurons (Hoffman et al., 1997). First, blockade of the transient
current with 4-AP dramatically increased the amplitude of dendritic
action potentials, although the high concentrations required are not completely selective for transient K+ channels.
Second, right-shifting the activation curve of the transient current by
protein kinases is associated with an increase in action potential
amplitude (Hoffman and Johnston, 1998). Third, computer simulations
suggest that the relatively slow activation kinetics of the sustained
currents have little effect on dendritic action potential amplitude
(Hoffman et al., 1997). Finally, the present results support a role for
transient channels in shaping the dendritic action potential. Block of
transient K+ channels increased dendritic action
potential amplitude although the sustained K+
currents increased.
In addition to providing postsynaptic depolarization sufficient to open
NMDA-receptor channels, back-propagating action potentials, if
sufficiently large, lead to an influx of Ca+ in the
dendrites (Spruston et al., 1995; Tsubokawa and Ross, 1997; Magee et
al., 1998). Although the exact importance is unclear, block of L-type
Ca+ channels reduces synaptic plasticity in at least
one paradigm (Magee and Johnston, 1997). Under conditions in which
dendritic K+ channels are reduced in number, for
example by 4-AP, this activation of Ca2+ channels
can lead to sustained depolarizations, firing, and even death of the
cell. Thus, if the neuron is to allow a relatively large spike to
propagate, it must still maintain electrical stability in the
dendrites. A shift in the activation range of transient channels
(Hoffman and Johnston, 1998) results in a larger action potential, but
the increase in spike amplitude opens more K+
channels, resulting in controlled excitability. In the case of arachidonic acid (or 4-AP), however, there is a block of the channels rather than a shift in the activation curve. Under these conditions, stability can be lost (as in Fig. 10) because additional depolarization activates fewer channels at all potentials. One solution for the cell
to maintain stability would be to provide an additional current one with kinetics too slow to reduce the amplitude of the dendritic action
potential. In the present study, we have observed such an effect in the
presence of arachidonic acid. The rapidly-activating, transient, A-type
currents are reduced while the slower, sustained currents are enhanced.
Consequently, the dendritic action potential is larger and can bring in
more Ca2+, but the likelihood of prolonged or
uncontrolled spikes is diminished.
Effects of arachidonic acid have been reported on a number of different
channel types in a number of different cells (Meves, 1994). In addition
to the block of transient K+ channels (Villarroel
and Schwarz, 1996; Keros and McBain, 1997; Dryer et al., 1998),
arachidonic acid has been shown to activate large conductance channels
(>100 pS) directly in cardiac muscle (Kim and Clapham, 1989) and in
visual cortical neurons (Horimoto et al., 1997), a small conductance
channel (23 pS) in smooth muscle (Ordway et al., 1989),
BK(Ca) channels in rat pituitary cells (Duerson et al.,
1996), and M-current through lipoxygenase or cyclooxygenase metabolites
in hippocampal neurons (Schweitzer et al., 1990). Thus, the present
results extend the list of effects of arachidonic acid on
K+ channels and provide some insight into the
physiological function of altering the relative availability of
different K+ channel classes.
Although its role in synaptic plasticity remains undefined, arachidonic
acid clearly plays a role in altering excitability under conditions
that induce long-term potentiation. Arachidonic acid has been shown to
modulate synaptic transmission by potentiating NMDA receptor currents
(Miller et al., 1992), increasing glutamate release (McGahon and Lynch,
1996), and inhibiting reuptake of amino acids (Breukel et al., 1997).
In fact, it has been argued that a replaceable loss of arachidonic acid
in the cell membrane during aging makes the induction of experimental
synaptic plasticity more difficult (McGahon et al., 1997). Also
relevant to signaling, arachidonic acid appears to modulate both high-
and low-threshold Ca2+ channels (Keyser and Alger,
1990; Meves, 1994). Thus, the redistribution of available
K+ channel conductances seen here is part of a
larger constellation of effects of arachidonic acid to alter the
excitability and function of the cell under specific conditions.
Comparing the present results with those of Keros and McBain (1997)
highlights the spatial differences in activity and function in the
subcellular compartments of the neuron. Although Keros and McBain
demonstrated a strong effect of arachidonic acid on the isolated
somatic transient K+ current, they observed little
or no effect on somatic action potentials recorded in normal
conditions. Rather than being contradictory, the differences in the
effects on the somatic and dendritic action potentials are consistent
with slower kinetics of the dendritic action potential and the fivefold
difference in transient K+ channel density found
across the somatodendritic axis (Hoffman et al., 1997).
| |
FOOTNOTES |
Received June 1, 1999; revised July 9, 1999; accepted July 12, 1999.
This work was supported by National Institute of Health Grant NS36982.
We thank S. Dryer for comments on an earlier version of this
manuscript, J. C. Magee for suggesting the 4-AP experiment, M. Ho for
technical assistance, C. J. McBain for helpful discussions regarding
the stability of ETYA, and G. W. G. Chase for encouragement early in
this study.
Correspondence should be addressed to Dr. Costa M. Colbert, Department
of Biology and Biochemistry, University of Houston, 4800 Calhoun Road,
Houston, TX 77204-5513.
| |
REFERENCES |
-
Breukel AI,
Besselsen E,
Lopes da Silva FH,
Lopes da Silva FH,
Ghijsen WE
(1997)
Arachidonic acid inhibits uptake of amino acids and potentiates PKC effects on glutamate, but not GABA, exocytosis in isolated hippocampal nerve terminals.
Brain Res
773:90-97[Medline].
-
Buzsáki G,
Kandel A
(1998)
Somadendritic backpropagation of action potentials in cortical pyramidal cells of the awake rat.
J Neurophysiol
79:1587-1591[Abstract/Free Full Text].
-
Buzsáki G,
Penttonen M,
Nádasdy Z,
Bragin A
(1996)
Pattern and inhibition-dependent invasion of pyramidal cell dendrites by fast spikes in the hippocampus in vivo.
Proc Natl Acad Sci USA
93:9921-9925[Abstract/Free Full Text].
-
Callaway JC,
Ross WN
(1995)
Frequency-dependent propagation of sodium action potentials in dendrites of hippocampal CA1 pyramidal neurons.
J Neurophysiol
74:1395-1403[Abstract/Free Full Text].
-
Colbert CM,
Magee JC,
Hoffman DA,
Johnston D
(1997)
Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons.
J Neurosci
17:6512-6521[Abstract/Free Full Text].
-
Dryer L,
Xu Z,
Dryer SE
(1998)
Arachidonic acid-sensitive A-currents and multiple Kv4 transcripts are expressed in chick ciliary ganglion neurons.
Brain Res
789:162-166[Web of Science][Medline].
-
Duerson K,
White RE,
Jiang F,
Schonbrunn A,
Armstrong DL
(1996)
Somatostatin stimulates BKCa channels in rat pituitary tumor cells through lipoxygenase metabolites of arachidonic acid.
Neuropharmacology
35:949-961[Web of Science][Medline].
-
Hoffman DA,
Johnston D
(1998)
Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC.
J Neurosci
18:3521-3528[Abstract/Free Full Text].
-
Hoffman DA,
Johnston D
(1999)
Neuromodulation of dendritic action potentials.
J Neurophysiol
81:408-411[Abstract/Free Full Text].
-
Hoffman DA,
Magee JC,
Colbert CM,
Johnston D
(1997)
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.
Nature
387:869-875[Medline].
-
Horimoto N,
Nabekura J,
Ogawa T
(1997)
Arachidonic acid activation of potassium channels in rat visual cortex neurons.
Neuroscience
77:661-671[Medline].
-
Jaffe DB,
Johnston D,
Lasser-Ross N,
Lisman JE,
Miyakawa H,
Ross WN
(1992)
The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons.
Nature
357:244-246[Medline].
-
Keros S,
McBain CJ
(1997)
Arachidonic acid inhibits transient potassium currents and broadens action potentials during electrographic seizures in hippocampal pyramidal and inhibitory interneurons.
J Neurosci
17:3476-3487[Abstract/Free Full Text].
-
Keyser DO,
Alger BE
(1990)
Arachidonic acid modulates hippocampal calcium current via protein kinase C and oxygen radicals.
Neuron
5:545-553[Web of Science][Medline].
-
Kim D,
Clapham DE
(1989)
Potassium channels in cardiac cells activated by arachidonic acid and phospholipids.
Science
244:1174-1176[Abstract/Free Full Text].
-
Magee JC,
Johnston D
(1997)
A synaptically controlled, associative signal for hebbian plasticity in hippocampal neurons.
Science
275:209-213[Abstract/Free Full Text].
-
Magee J,
Hoffman D,
Colbert C,
Johnston D
(1998)
Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons.
Annu Rev Physiol
60:327-346[Web of Science][Medline].
-
Maletic-Savatic M,
Lenn NJ,
Trimmer JS
(1995)
Differential spatiotemporal expression of K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro.
J Neurosci
15:3840-3851[Abstract].
-
Markram H,
Lübke J,
Frotscher M,
Sakmann B
(1997)
Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs.
Science
275:213-215[Abstract/Free Full Text].
-
McGahon B,
Lynch MA
(1996)
The synergism between metabotropic glutamate receptor activation and arachidonic acid on glutamate release is occluded by induction of long-term potentiation in the dentate gyrus.
Neuroscience
72:847-855[Web of Science][Medline].
-
McGahon B,
Clements MP,
Lynch MA
(1997)
The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed.
Neuroscience
81:9-16[Web of Science][Medline].
-
Meves H
(1994)
Modulation of ion channels by arachidonic acid.
Prog Neurobiol
43:175-186[Web of Science][Medline].
-
Miller B,
Sarantis M,
Traynelis SF,
Attwell D
(1992)
Potentiation of NMDA receptor currents by arachidonic acid.
Nature
355:722-725[Medline].
-
Ordway RW,
Walsh JV,
Singer Jr. JJ
(1989)
Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells.
Science
244:1176-1179[Abstract/Free Full Text].
-
Schweitzer P,
Madamba S,
Siggins GR
(1990)
Arachidonic acid metabolites as mediators of somatostatin-induced increase of neuronal M-current.
Nature
346:464-467[Medline].
-
Serôdio P,
Miera EV-SD,
Rudy B
(1996)
Cloning of a novel component of A-type K+ channels operating a subthreshold potentials with unique expression in heart and brain.
J Neurophysiol
75:2174-2179[Abstract/Free Full Text].
-
Sheng M,
Tsaur M-L,
Jan YN,
Jan LY
(1992)
Subcellular segregation of two A-type K+ channel proteins in rat central neurons.
Neuron
9:271-284[Web of Science][Medline].
-
Spruston N,
Schiller Y,
Stuart G,
Sakmann B
(1995)
Activity-dependent action potential invasion and calcium influx into hippocampal CA1 dendrites.
Science
268:297-300[Abstract/Free Full Text].
-
Stuart GJ,
Sakmann B
(1994)
Active propagation of somatic action potentials into neocortical pyramidal cell dendrites.
Nature
367:69-72[Medline].
-
Stuart GJ,
Dodt HU,
Sakmann B
(1993)
Patch-clamp recordings from the soma and dendrites of neurones in brain slices using infrared video microscopy.
Pflügers Arch
423:511-518[Web of Science][Medline].
-
Stuart G,
Spruston N,
Sakmann B,
Häusser M
(1997)
Action potential initiation and backpropagation in neurons of the mammalian CNS.
Trends Neurosci
20:125-131[Web of Science][Medline].
-
Svoboda K,
Denk W,
Kleinfeld D,
Tank DW
(1997)
In vivo dendritic calcium dynamics in neocortical pyramidal neurons.
Nature
385:161-165[Medline].
-
Tsubokawa H,
Ross WN
(1996)
IPSPs modulate spike backpropagation and associated [Ca2+]i changes in the dendrites of hippocampal CA1 pyramidal neurons.
J Neurophysiol
76:2896-2906[Abstract/Free Full Text].
-
Tsubokawa H,
Ross WN
(1997)
Muscarinic modulation of spike backpropagation in the apical dendrites of hippocampal CA1 pyramidal neurons.
J Neurosci
17:5782-5791[Abstract/Free Full Text].
-
Turner RW,
Meyers DER,
Richardson TL,
Barker JL
(1991)
The site for initiation of action potential discharge over the somatodendritic axis of rat hippocampal CA1 pyramidal neurons.
J Neurosci
11:2270-2280[Abstract].
-
Villarroel A,
Schwarz TL
(1996)
Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid.
J Neurosci
16:1016-1025[Abstract/Free Full Text].
Copyright © 1999 Society for Neuroscience 0270-6474/99/19198163-09$05.00/0
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|
M. H. Holmqvist, J. Cao, M. H. Knoppers, M. E. Jurman, P. S. Distefano, K. J. Rhodes, Y. Xie, and W. F. An
Kinetic Modulation of Kv4-Mediated A-Current by Arachidonic Acid Is Dependent on Potassium Channel Interacting Proteins
J. Neurosci.,
June 15, 2001;
21(12):
4154 - 4161.
[Abstract]
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L. Liu, C. F. Barrett, and A. R. Rittenhouse
Arachidonic acid both inhibits and enhances whole cell calcium currents in rat sympathetic neurons
Am J Physiol Cell Physiol,
May 1, 2001;
280(5):
C1293 - C1305.
[Abstract]
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E. Pan and C. M. Colbert
Subthreshold Inactivation of Na+ and K+ Channels Supports Activity-Dependent Enhancement of Back-Propagating Action Potentials in Hippocampal CA1
J Neurophysiol,
February 1, 2001;
85(2):
1013 - 1016.
[Abstract]
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M. Zhu, R. Natarajan, J. L. Nadler, J. M. Moore, C. H. Gelband, and C. Sumners
Angiotensin II Increases Neuronal Delayed Rectifier K+ Current: Role of 12-Lipoxygenase Metabolites of Arachidonic Acid
J Neurophysiol,
November 1, 2000;
84(5):
2494 - 2501.
[Abstract]
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J. M Bekkers
Distribution and activation of voltage-gated potassium channels in cell-attached and outside-out patches from large layer 5 cortical pyramidal neurons of the rat
J. Physiol.,
June 15, 2000;
525(3):
611 - 620.
[Abstract]
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D. Johnston, D. A Hoffman, J. C Magee, N. P Poolos, S. Watanabe, C. M Colbert, and M. Migliore
Dendritic potassium channels in hippocampal pyramidal neurons
J. Physiol.,
May 15, 2000;
525(1):
75 - 81.
[Abstract]
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J. Du, L. L Haak, E. Phillips-Tansey, J. T Russell, and C. J McBain
Frequency-dependent regulation of rat hippocampal somato-dendritic excitability by the K+ channel subunit Kv2.1
J. Physiol.,
January 1, 2000;
522(1):
19 - 31.
[Abstract]
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TOP
ABSTRACT
INTRODUCTION
