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The Journal of Neuroscience, May 15, 1998, 18(10):3521-3528
Downregulation of Transient K+ Channels in Dendrites
of Hippocampal CA1 Pyramidal Neurons by Activation of PKA and
PKC
Dax A.
Hoffman and
Daniel
Johnston
Division of Neuroscience, Baylor College of Medicine, Houston,
Texas 77030
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ABSTRACT |
We have reported recently a high density of transient A-type
K+ channels located in the distal dendrites of CA1
hippocampal pyramidal neurons and shown that these channels shape
EPSPs, limit the back-propagation of action potentials, and
prevent dendritic action potential initiation (Hoffman et al., 1997 ).
Because of the importance of these channels in dendritic signal
propagation, their modulation by protein kinases would be of
significant interest. We investigated the effects of activators of
cAMP-dependent protein kinase (PKA) and the
Ca2+-dependent phospholipid-sensitive protein kinase
(PKC) on K+ channels in cell-attached patches from
the distal dendrites of hippocampal CA1 pyramidal neurons. Inclusion of
the membrane-permeant PKA activators 8-bromo-cAMP (8-br-cAMP) or
forskolin in the dendritic patch pipette resulted in a depolarizing
shift in the activation curve for the transient channels of ~15 mV.
Activation of PKC by either of two phorbol esters also resulted in a 15 mV depolarizing shift of the activation curve. Neither PKA nor PKC
activation affected the sustained or slowly inactivating component of
the total outward current. This downregulation of transient
K+ channels in the distal dendrites may be
responsible for some of the frequently reported increases in cell
excitability found after PKA and PKC activation. In support of this
hypothesis, we found that activation of either PKA or PKC significantly
increased the amplitude of back-propagating action potentials in distal dendrites.
Key words:
potassium channels; IK(A); dendrite; protein kinase A; protein kinase C; hippocampus; phorbol
esters; cAMP; action potential
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INTRODUCTION |
Voltage-dependent
K+ channels are the primary regulators of membrane
excitability. As a group, they constitute the most diverse of the
voltage-gated channels (Rudy, 1988). The large repertoire of
K+ channel subtypes available may underlie the
distinctive firing patterns expressed by different neurons and by the
same cells under different conditions. We have recently found a
transient A-type K+ channel to be expressed at high
densities in the distal dendrites of CA1 pyramidal neurons (Hoffman et
al., 1997). Modulation of these channels could provide the neuron with
the means to dynamically and selectively control signal propagation
through the dendrites.
The molecular identity of the transient K+ channels
recorded in the CA1 hippocampal dendrites is not known for certain,
although there is strong evidence in favor of the Shal
channel Kv4.2. Of the two transient K+ channels
Kv4.2 and Kv1.4 found in the hippocampus by immunohistochemical techniques, Kv4.2 is primarily located in the soma and dendrites (with
the highest degree of immunostaining occurring in dendrites), whereas
Kv1.4 is found mainly in axons (Sheng et al., 1992; Maletic-Savatic et
al., 1995; Serôdio et al., 1996). Kv4.2 has also been found clustered on the postsynaptic membrane directly apposed to the presynaptic terminal (Alonso and Widmer, 1997). Additionally, both
Kv4.2 and the transient K+ channels recorded from
CA1 somata are inhibited by arachidonic acid (Villaroel and Schwarz,
1996; Keros and McBain, 1997). Finally, Serôdio et al. (1994)
demonstrate that hydrogen peroxide blocks the inactivation of Kv1.4 but
not of Kv4.2 channels. Inactivation of the transient channels recorded
in CA1 hippocampal neurons is unaffected by externally applied hydrogen
peroxide (D. Hoffman, unpublished observations). In our previous report
(Hoffman et al., 1997), transient K+ channels in
distal dendrites were found to have an activation curve shifted 10-15
mV hyperpolarized compared with those recorded from the soma and
proximal (up to 100 µm) dendrites. This result suggested that either
a different type of channel is expressed in the two regions or that
there is only one channel type, but one that is differentially
modulated in the two regions. The immunohistochemical studies that
found Kv4.2 located in both the soma and dendrites would support the
later conclusion (Sheng et al., 1992; Maletic-Savatic et al., 1995;
Serôdio et al., 1996).
Activators of protein kinase A (PKA) and protein kinase C (PKC) have
been found to increase the amplitude of EPSPs and population spikes in
hippocampal neurons (Malenka et al., 1986; Hu et al., 1987; Storm,
1987; Hvalby et al., 1988; Heginbotham and Dunwiddie, 1991; Slack and
Pockett, 1991; Dunwiddie et al., 1992; Pockett et al., 1993). Because
the amino acid sequence of Kv4.2 has been shown to contain a potential
site for PKA phosphorylation and numerous potential PKC sites (Baldwin
et al., 1991; Blair et al., 1991; Anderson et al., 1997), we
hypothesized that phosphorylation of transient dendritic
K+ channels could potentially account for some of
these electrophysiological changes. To test this hypothesis, we made
cell-attached patch-clamp recordings of K+ currents
from CA1 hippocampal dendrites (180-340 µm from the soma) with and
without the inclusion of membrane-permeant activators of both PKA and
PKC in the recording pipette. The results suggest that activation of
either PKA or PKC can downregulate these channels by shifting the
activation curve to more positive potentials. As a test for the
functional significance of this downregulation, dendritic action
potentials were recorded before and after bath application of PKA and
PKC activators. After activation of either kinase, dendritic action
potential amplitude was found to increase over 50% in distal
dendrites, consistent with a decrease in K+ channel
activation.
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MATERIALS AND METHODS |
Preparation and solutions. Sprague Dawley
rats, 5-8 weeks old, were anesthetized with a lethal dose of a
combination of ketamine, xylazine, and acepromazine. After they were
deeply anesthetized, they were perfused through the heart with
cold-modified artificial CSF (ACSF) containing (in mM): 110 CholineCl, 2.5 KCl, 1.2 NaH2PO4, 25 NaHCO3, 0.5 CaCl2, 7.0 MgCl2, 2.4 pyruvate, 1.3 ascorbic acid, and 20 dextrose. After removal of the brain, 400-µm-thick slices were cut
using a vibratome, incubated submerged in a holding chamber for 10 min
at 34°C, and stored and used for recordings at room temperature.
Hippocampal slices were visualized with a Zeiss Axioskop using infrared
video microscopy and differential interference contrast optics. For all
recordings, the bath solution contained (in mM): 125 NaCl,
2.5 KCl, 1.25 NaH2PO4, 25 NaHCO3, 2.0 CaCl2, 1.0 MgCl2, and 25 dextrose. In whole-cell experiments,
the following were included in the external solution to block synaptic
transmission (in µM): 50 D,L-APV (Research
Biochemicals, Natick, MA), 20 MK-801 (Research Biochemicals), 10 CNQX
(Research Biochemicals), 10 bicuculline (Sigma, St. Louis, MO), and 10 picrotoxin (Sigma). The external solution was bubbled with 95%
O2/5% CO2 at ~22°C, pH ~7.4. For cell-attached recordings, the normal pipette solution consisted of 125 mM NaCl, 10 mM HEPES, 2.0 mM
CaCl2, 1.0 mM MgCl2,
2.5 mM KCl, and 1.0 µM tetrodotoxin (TTX), pH
7.4 with NaOH, to which 100 µM 8-bromo-cAMP (8-br-cAMP;
Sigma) was included in certain experiments. For forskolin (Sigma) and
phorbol ester (Sigma) recordings, drugs were dissolved in DMSO to 10 mM, kept frozen until use, and then diluted to the
appropriate concentration. Whole-cell recording pipettes (10-15 M )
were filled with (in mM): 120 KGluconate, 20 KCl, 10 HEPES,
2 MgCl2, 4 Mg-ATP, 0.3 Mg-GTP, and 14 phosphocreatine, pH
7.25 with KOH; pipettes were coated with Sylgard.
1-(5-isoquinolinylsulfonyl)2methyl-piperazine dichloride (300 µM; Sigma) and 8-br-cAMP were dissolved directly into the
external bath solution in whole-cell experiments.
Recording techniques and analysis. All neurons exhibited a
resting membrane potential between  55 and 73 mV (mean, 66 mV). Cell-attached pipettes (10-20 M) were pulled from borosilicate glass and coated with Sylgard. The tips were visually inspected before
use and had uniform tip diameters of ~1 µm. Channel recordings, using an Axopatch 1D amplifier (Axon Instruments), were analog filtered
at 2 kHz and digitally filtered at 1 kHz off-line. Leakage and
capacitive currents were digitally subtracted by averaging null traces
or scaling traces of similar amplitude. Whole-cell patch-clamp
recordings were made using an Axoclamp 2A (Axon Instruments) amplifier
in "bridge" mode, low-pass filtered at 3 kHz, and digitized at 10 kHz. Series resistance was 15-40 M. Antidromic action potentials were stimulated by constant current pulses (Neurolog; Digitimer Ltd.)
through tungsten electrodes (AM Systems) placed in the alveus.
For activation plots, the chord conductance, as calculated from the
peak ensemble current amplitude from a holding potential of
approximately 85 mV, was normalized to the maximum value and plotted
as a function of the test potential. In the case in which the maximal
voltage step did not result in a saturated conductance, conductances
were fit to a single Boltzmann, and the peak conductance was used for
normalization. For inactivation, the peak ensemble current amplitude
for a step to approximately +55 mV was normalized to maximum and
plotted as a function of holding potential. Data were binned into
either 10 or 20 mV compartments. Curves are nonlinear least-square fits
of the data to Boltzmann functions. Inactivation time constants were
fit using the Fourier expansion method DISCRETE (Provencher, 1976) and
were well fit by a single exponential in most cases. Significance
(p < 0.05) was determined by two-sample t tests in all cases except for the PDA effect on action
potential amplitude in which a paired t test was used. Error
bars represent SEM, and voltages were not corrected for the junction
potential (approximately 7 mV).
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RESULTS |
Isolation of the transient current
Cell-attached patch-clamp recordings from CA1 hippocampal
dendrites, in the presence of TTX to block voltage-gated
Na+ channels, revealed a large outward current
composed of a rapidly inactivating component along with a sustained or
slowly inactivating component. Although the transient current
IK(A) was from three to five times the amplitude
of the sustained current in the distal dendrites, the transient current
was routinely isolated from the sustained current by the voltage
protocol shown in Figure 1. In a typical
experiment, the patch was held 20 mV hyperpolarized to rest and
subsequently depolarized by 20-140 mV in 20 mV increments. Ensemble
averages were constructed of 10-30 sweeps per step potential. At the
conclusion of the experiment, the membrane was ruptured, and the
resting membrane potential was measured, allowing for conversion of the
voltage steps relative to rest into absolute voltages. The total
outward current recorded for a voltage step from 89 to +51 mV is
shown in Figure 1A. A 50 msec prepulse to 29 mV
allowed the transient channels to inactivate, leaving only the
sustained current (Fig. 1B). The sustained current
was subsequently digitally subtracted from the total outward current,
resulting in the isolated transient current (Fig. 1C).
Occasionally, when a full prepulse ensemble was not obtained, the
transient component was taken to be the peak of the total current
measured 2 msec into the pulse (before substantial sustained component
activation). Activation and inactivation curves constructed using this
method were similar to those using prepulses. All channel recordings were made 180-340 µm from the soma.
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Figure 1.
Procedure for isolating the transient current in
cell-attached patches. A, The total outward current from
a dendritic patch located 320 µm from the soma for a 150 msec voltage
step from 89 to +51 mV is shown. Voltage protocol is shown
above the trace. Here and in subsequent
figures, traces are ensemble averages of 10-30 sweeps.
B, A 50 msec prepulse (VPP) to 29
mV results in transient channel inactivation, leaving only the
sustained component of the total outward current. C,
Digital subtraction of the current remaining in B from
that in A results in the isolated transient component
shown.
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Modulation of transient K+ channels by
activators of PKA
To test for modulation by PKA, we included 100 µM
8-br-cAMP, a membrane soluble analog of cAMP, in the patch pipette in
12 dendritic cell-attached recordings. Representative traces (scaled to
represent their fraction of maximal conductance) from both control and
8-br-cAMP recordings are shown in Figure
2A. In control conditions, a voltage step to 5 mV (near the peak voltage reached during an action potential) activates nearly 50% of the available channels. The inclusion of 8-br-cAMP in the patch pipette reduced this
fraction to ~25%. In the same cell, subsequent bath application of
300 µM H7, a protein kinase inhibitor, increased the
fraction back toward control levels. Steady-state activation and
inactivation curves were generated from these experiments and are
illustrated in Figure 2B. Adding 8-br-cAMP to the
patch pipette produced a 13 mV rightward shift in the activation curve,
presumably via the activation of PKA (V1/2, 2 and
+11 mV for control and 8-br-cAMP, respectively; Fig.
2B; Table 1). Similar
effects were seen when 50 µM forskolin, an adenylyl
cyclase activator, was included in the dendritic patch pipette
(V1/2 = +7 mV; n = 5; Table 1). A rightward
shift in the activation curve means that at any given potential there
will be a decrease in the probability of channel opening. We also found
the inactivation curve to be shifted slightly but significantly toward
the right (V1/2, 56 vs 50 mV for control and
8-br-cAMP, respectively; Fig. 2B; Table 1). In three
of the 12 8-br-cAMP experiments, the kinase inhibitor H7 was bath
applied after obtaining a full activation curve. Under these
conditions, the activation curve was found to shift progressively back
toward control levels in a time-dependent manner (V1/2 = +3.5 mV after 30 min in H7; Fig. 2B; Table 1). Two of
the three patches were lost before complete reversal of the 8-br-cAMP
effect. On one occasion, however, the patch was held for nearly 1 hr
after H7 application. In this patch the curve shifted completely back
to control levels (V1/2 = 2 mV; Fig.
2B, inset). These results indicate that
the shift in the activation curve is attributable to kinase activation
and not just a direct effect of 8-br-cAMP on the channel. No
significant difference in resting membrane potential was found among
groups (Table 1).
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Figure 2.
Downregulation of transient channel activation by
PKA activation. A, Representative example of isolated
transient currents for the control condition and for that with 100 µM 8-br-cAMP included in the patch pipette, scaled to
demonstrate their fraction of maximal conductance, for a step from 85
to 5 mV. Under control conditions, nearly 50% of the available
channels are activated by this voltage step. With PKA activation, only
~25% are activated. In the same patch, subsequent H7 application
returned the fraction of channels activated back toward control levels.
B, Steady-state activation and inactivation curves for
control and 8-br-cAMP conditions and an activation curve for the
condition with 8-br-cAMP in the pipette after bath application of 300 µM H7. Half-activation with 8-br-cAMP (V1/2 = +11 mV; n = 12) was shifted 13 mV to the
right of control levels (V1/2 = 2 mV;
n = 12). There was also a small (6 mV) shift
in the inactivation curve with 8-br-cAMP (V1/2 = 50 mV and n = 8 vs V1/2 = 56 mV and
n = 5 for controls). Bath application of H7 shifted
the 8-br-cAMP curve back toward control levels (V1/2 = +3.5 mV after 30 min in H7; n = 3).
Inset, Time course of reversal of PKA effect by H7
application (top horizontal bar). The activation and
inactivation curves under control conditions are nearly identical to
those reported previously for transient K+ channels
in distal dendrites (Hoffman et al., 1997). Curves (here and see Figs.
3, 5, 6) are least-square fits of the data to Boltzmann functions (see
Materials and Methods).
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Modulation of transient K+ channels by
phorbol esters
We investigated the effects of PKC activation on these channels by
including one of two different phorbol esters in the patch pipette.
Both phorbol diacetate (PDA, 10 µM) and phorbol
dibutyrate (PDBu, 10 µM) were found to produce a 15 mV
depolarizing shift in the activation curve for transient
K+ channels located in the distal dendrites, very
similar to that found for PKA activation. Representative traces, scaled
to represent their fraction of maximal conductance, from both control
and PDA recordings are shown in Figure
3A. The inclusion of PDA in
the patch pipette led to a 15 mV rightward shift in the activation curve, presumably via the activation of PKC (V1/2,
2 and +13 mV for control and PDA, respectively; Fig. 3B;
Table 1). Again, this shift would have the effect of decreasing the
probability of channel opening at a given potential. As was the case
for PKA activation, there was also a small but significant (6 mV)
depolarizing shift in the inactivation curve in the presence of PDA
(V1/2, 56 vs 50 mV for control and PDA,
respectively; Fig. 3B; Table 1). The steady-state activation
curve produced with PDBu in the pipette also was found to be shifted by
~14 mV (V1/2 = +12 mV; Fig. 3B; Table 1).
There was, however, no shift in the activation curve when the inactive
phorbol ester 4- -phorbol was included in the pipette
(V1/2 = 2 mV; Fig. 3B; Table 1). These results indicate that the shift in the activation curve is attributable to
kinase activation rather than to nonspecific effects of phorbol esters
on the channels. Again, no significant difference in resting membrane
potential was found among the groups (Table 1).
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Figure 3.
Downregulation of transient channel
activation by PKC activation. A, Representative example
of isolated transient currents for the control condition and for that
with 10 µM PDA included in the patch pipette, scaled to
demonstrate their fraction of maximal conductance, for a step from 85
to 5 mV. B, Steady-state activation and inactivation
curves for control and two different phorbol ester conditions.
Half-activation with PDA (V1/2 = +13 mV;
n = 7) or PDBu (V1/2 = +12 mV;
n = 4) was shifted ~15 mV to the
right of controls (V1/2 = 2 mV;
n = 12). There was also a small (6 mV) shift in the
inactivation curve with PDA (V1/2 = 50 mV and
n = 6 vs V1/2 = 56 mV and
n = 5 for controls). There was, however, no
activation curve shift when the inactive phorbol ester 4--phorbol
was included in the pipette (V1/2 = 2 mV;
n = 8).
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The voltage dependency of inactivation is altered by 8-br-cAMP
and PDA
We have reported previously that the time constant of inactivation
of the transient current increases with membrane potential (Hoffman et
al., 1997). The same voltage dependency was found in the present study
in which the time constant of inactivation for the transient component
increased linearly with the amount of depolarization from 11.9 ± 0.9 msec for a step to 5 mV to 27.9 ± 2.3 msec for a step to
+55 mV under control conditions (slope = 2.5 msec/10 mV; Fig.
4). Inclusion of either 8-br-cAMP or PDA
in the patch pipette resulted in a more shallow slope (1.9 msec/10 mV).
The time constant at 5 mV was similar to the control value (11.3 ± 0.6 and 10.2 ± 0.9 msec for 8-br-cAMP and PDA, respectively) but was significantly faster than the control value at +55 mV (22.6 ± 2.1 and 22.1 ± 1.6 msec; Fig. 4). Traces from the
PDBu group of experiments had time constants of inactivation similar to
that of the PDA and 8-br-cAMP groups (slope = 2.0 msec/10 mV), and
the inactivation rates in the 4--phorbol traces were similar to that
of controls (2.5 msec/10 mV; data not shown).
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Figure 4.
Both 8-br-cAMP and PDA alter the voltage
dependency of inactivation for the transient channels. Time constants
for inactivation are plotted versus membrane potential for control,
8-br-cAMP, and PDA. Time constants for control and drug conditions were
similar for the smallest depolarization measured (5 mV) but were
significantly different at higher potentials, resulting in a shallower
slope of the lines fit to the data. Slope equals 2.5 msec/10 mV for control and 1.9 msec/10 mV for both 8-br-cAMP and PDA
conditions. Inset, Two traces, scaled to
the same amplitude, for a step to +55 mV under control (bottom
trace) and 8-br-cAMP (top trace) conditions fit
by a single exponential ( , 30.7 and 20.6 msec for control and
8-br-cAMP, respectively).
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The peak current level from which the time constant was measured is a
result of both activation and inactivation kinetics. It seemed possible
that this change in slope was the result of incomplete activation under
the active kinase conditions. This possibility was ruled out, however,
by also measuring the time constant 20 msec into the trace (when
activation is presumably complete). The time constants measured in this
manner were similar to those measured from the peak current level.
The effects of 8-br-cAMP and PDA on transient channel activation
are not additive
In five patches, both 8-br-cAMP and PDA were included the patch
pipette. The results, shown in Figure 5,
indicate that the effects of the two agents are not additive
but rather resemble the shifts seen with either 8-br-cAMP or PDA alone.
Representative traces, scaled to represent their fraction of maximal
conductance, from both control and PDA with 8-br-cAMP recordings are
shown in Figure 5A. The activation curve for 8-br-cAMP plus
PDA was shifted to the right by 10 mV compared with that for controls (Fig. 5B; Table 1).
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Figure 5.
The effects of PKA and PKC activation are not
additive. A, Representative example of isolated
transient currents for the control condition and for that with 100 µM 8-br-cAMP plus 10 µM PDA included in the
patch pipette, scaled to demonstrate their fraction of maximal
conductance, for a step from 85 to 5 mV. B,
Steady-state activation and inactivation curves for control and
8-br-cAMP plus PDA. Half-activation with 8-br-cAMP plus PDA
(V1/2 = +8 mV; n = 5) was shifted 10 mV
to the right of control levels (V1/2 = 2
mV; n = 7). There was also a small (5 mV) shift in
the inactivation curve with 8-br-cAMP plus PDA (V1/2 = 51
mV and n = 3 vs V1/2 = 56 mV and
n = 5 for controls).
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The sustained component is not affected by either 8-br-cAMP
or PDA
We also examined the effect of including 8-br-cAMP and PDA in the
patch pipette on the sustained component of the total outward current.
Ensemble averages of the current remaining at the end of the pulse were
used to construct an activation curve for the sustained component. The
half-activation values of +2, +7, and +5 mV for control
(n = 10), 8-br-cAMP (n = 6), and PDA
(n = 8) conditions, respectively, were not
significantly different (Fig. 6).
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Figure 6.
The sustained current was unaffected by either
8-br-cAMP or PDA. Steady-state activation curves for the sustained
component are plotted for control, 8-br-cAMP, and PDA. Half-activation
with 8-br-cAMP (V1/2 = +7 mV; k = 10.5;
n = 6) and PDA (V1/2 = +5 mV;
k = 8.5; n = 8) was similar to
that with controls (V1/2 = +2 mV;
k = 8.5; n = 10). Note that the
difference in V1/2 between control and 8-br-cAMP conditions
was primarily caused by the small difference in fitted slope, although
this slope change was not significant.
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PKA or PKC activation increases the back-propagating action
potential amplitude
Dendritic, whole-cell patch recordings of antidromically initiated
action potentials were made to assess the functional impact of
decreasing the transient K+ channel activity by
protein kinase activation. Action potential amplitude, known to
decrease with distance from the soma because of an increasing density
of A-channels (Turner et al., 1991; Andreasen and Lambert, 1995;
Spruston et al., 1995; Hoffman et al., 1997; Magee and Johnston, 1997),
was measured before and after bath application of PKA and PKC
activators. In distal dendrites, where the amplitude is significantly
attenuated by A-channels, both PKA and PKC activation led to a
substantial increase in action potential amplitude (Fig.
7). Action potential amplitude increased by an average of 78 ± 15% after 10 µM PDA
application in distal recordings (Fig.
7A,C). In Figure 7A, PKC
activation increased action potential amplitude by 62% in a recording
240 µm from the soma. In these experiments, the cell was
hyperpolarized to 80 mV to remove residual Na+
channel inactivation, which has been shown to be affected by PKC
activation (Colbert et al., 1997; Colbert and Johnston, 1998). It has
been reported previously that PKC activation does not lead to a
significant increase in action potential amplitude in more proximal
recordings (Colbert and Johnston, 1998). Similarly, in proximal
dendrites, 100 µM 8-br-cAMP had little effect on action potential amplitude in contrast to distal recordings in which the
action potential was increased by an average of 51 ± 14% (Fig. 7B,C). In Figure 7B, PKA
activation increased action potential amplitude by 42% in a recording
280 µm from the soma but had no effect on the action potential
recorded 150 µm from the soma. Recordings made at locations in
between those shown in Figure 7B resulted in an intermediate
but significant increase in action potential amplitude (Fig.
7C). Inclusion of H7 in the external solution to oppose
kinase activation prevented the effect of 8-br-cAMP on action potential
amplitude (Fig. 7C).
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Figure 7.
PKA and PKC activation increases the
back-propagating action potential amplitude in the distal dendrites.
A, Antidromically initiated action potentials before
(pre) and after (+PDA) bath
application of 10 µM PDA. In this recording 240 µm from
the soma, application of PDA lead to a 62% increase in action
potential amplitude (from 44 to 71 mV). B,
Antidromically initiated action potentials before
(pre) and after (post and
+8-br-cAMP) bath application of 100 µM
8-br-cAMP. Left, In a more proximal recording (150 µm
from the soma), in which A-channel density is smaller, action potential
amplitude was large to begin with, and 8-br-cAMP did not lead to an
increase in amplitude. Right, In this distal recording
(280 µm from the soma), in which action potential amplitude is
attenuated because of high A-channel density, PKA activation increased
the amplitude over 40% (from 33 to 47 mV). C, Summary
data. Percent change in action potential amplitude and maximal rate of
rise are plotted for five conditions: distal recordings after PDA
application, proximal (150 µm) recordings after 8-br-cAMP
application, mid (180-200 µm) recordings after 8-br-cAMP
application, distal (250-320 µm) recordings after 8-br-cAMP
application, and distal and mid recordings after 8-br-cAMP application
with 300 µM H7 included in the external solution. The
number of cells for each group is in
parentheses. Asterisks denote a
significant percent increase over the controls (see Materials and
Methods).
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The increase in action potential amplitude occurred without a
significant increase in the rate of rise. This along with the lack of
PKA effect on proximally recorded action potentials indicates that the
kinase-dependent increase in amplitude is not caused by an increase in
Na+ conductance (Hodgkin and Katz, 1949). This
action potential augmentation without an effect on rate of rise was
also found after blockade of A-channels by 4-aminopyridine (Hoffman et
al., 1997). These data suggest that depolarizing the A-channel
activation curve via phosphorylation by PKA or PKC allows dendritic
action potentials to propagate farther out into the dendrites than
would occur under control conditions.
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DISCUSSION |
In the present study, we report the downregulation of a
voltage-gated K+ channel by activators of two
protein kinases, PKA and PKC. Both 8-br-cAMP and forskolin, which
activate PKA, shifted the activation curve for dendritic, transient
K+ channels by ~15 mV toward depolarizing
potentials. A decrease in transient K+ channel
activation in the presence of cAMP activators was also suggested by
Deadwyler et al. (1995), although the degree to which activation was
decreased was not reported. We also report here that activation of PKC
results in a 15 mV shift in the same direction. A recent report has
found a PKC effect on Kv4.2 channels expressed in Xenopus
oocytes (Nakamura et al., 1997). However, they do not find a shift in
the activation curve but, rather, a simple suppression of currents.
Although these two findings both result in a decrease in A-current,
they are quite different. A shift in the activation curve is a change
in the voltage dependence of the probability of channel opening, which
indicates an effect on the activation gate of the channel. The decrease
in Kv4.2 currents in oocytes, however, was without an effect on the
steady-state inactivation curve or the time course of recovery from
inactivation, indicating a direct inhibition of the channels by PKC
(Nakamura et al., 1997). This difference may mean that transient
currents are somehow differentially regulated in the two preparations
(perhaps by auxiliary subunits) or that the currents recorded in CA1
dendrites are not the result of Kv4.2 expression. It seems unlikely,
however, that Kv4.2 is not at least partially responsible for the
dendritic A-currents given the numerous immunohistochemical studies
that find Kv4.2 expressed in dendrites, with much less staining of
other transient channels (Sheng et al., 1992; Maletic-Savatic et al.,
1995; Serôdio et al., 1996). Especially relevant is a recent
report showing that both PKA and PKC phosphorylate Kv4.2 (Anderson et
al., 1997). Both the C and N terminals of Kv4.2 were shown to be
substrates for PKA phosphorylation, and the C terminal is a substrate
for PKC phosphorylation.
After PKA or PKC activation, we also report a small but significant
depolarizing shift in the inactivation curves. Comparing the
inactivation curves for control and 8-br-cAMP conditions in Figure
2B, it seems that this shift will have little effect
on the channels when the cell is at rest (approximately 65 to 70 mV), with ~90% of the channels being available for activation. With
sustained depolarization, however, there would be a greater percent of
channels available for activation with the kinase activated. For
example, at 55 mV, only 50% of the channels are available in control
conditions compared with 70% with PKA activated. This shift may act to
partially compensate for the increased excitability produced by PKA and
PKC activation.
It is now well established that back-propagating action potentials in
dendrites of CA1 neurons become progressively smaller in amplitude the
farther they travel from the soma and may even fail to propagate beyond
distal branch points. This decrement in action potential amplitude is
found in vivo and in vitro in both the
hippocampus and neocortex (Turner et al., 1991; Andreasen and Lambert,
1995; Spruston et al., 1995; Buzsáki et al., 1996; Magee and
Johnston, 1997; Svoboda et al., 1997). Although the function of this
decrementing action potential is unclear, the high density of transient
K+ channels is thought to be primarily responsible
for this phenomenon in the hippocampus, because blocking the channels
with 4-aminopyridine results in back-propagating action potentials that
decrement much less with distance (Hoffman et al., 1997). A decrease in
action potential amplitude could also be accomplished by a decreasing density of Na+ channels. By increasing an outward
conductance rather than decreasing an inward conductance, however, the
cell is able to selectively propagate full amplitude action potentials
under certain conditions. Here, we demonstrate one such condition, in
which the downregulation of the A-channels by PKA or PKC activation
resulted in larger back-propagating action potentials. In a model of a
CA1 pyramidal neuron, even a 5 mV shift in the A-channel activation
curve was found to significantly increase action potential amplitude in the distal dendrites (M. Migliore, D. A. Hoffman, J. C. Magee, D. Johnston, unpublished observations). If A-channel modulation were to
occur selectively in specific regions of the dendritic tree, action
potential amplitude may be increased in those regions only, possibly to
the extent of preferentially invading one branch over another.
Neuromodulatory inputs into the distal dendrites (activating PKA via
dopamine, norepinephrine, or serotonin or PKC via muscarinic receptors)
may then be able to direct action potentials to specific regions of the
dendrite.
It has been reported that the pairing of back-propagating action
potentials with EPSPs increases dendritic action potential amplitude
and associated Ca2+ influx supralinearly. This
pairing was found to facilitate the induction of long-term potentiation
(LTP) at CA1 synapses (Magee and Johnston, 1997). We have suggested
previously that the mechanism for this EPSP-spike boosting could
involve A-channel inactivation (Hoffman et al., 1997). The rapid rate
of inactivation of A-channels occurring for small depolarizations such
as EPSPs can lead to the amplification of back-propagating action
potentials near the site of synaptic input. The present results suggest
that downregulation of the A-channels by protein kinase activation,
yielding larger dendritic action potentials, might also increase the
probability of LTP induction. With high concentrations of 4-AP, which
block ~80% of the total A-channel population, large EPSPs can induce dendritic action potential initiation (Hoffman et al., 1997). It seems
unlikely, however, that the 15 mV shift in the activation curve
reported here would in itself reduce the A-channel population to the
degree necessary for dendritic action potential initiation under normal
conditions. If the cell were to undergo a sustained depolarization,
such as occurs during bursting or during the tetanus used to elicit
LTP, the decreased population of A-channels resulting from kinase
activation might increase the likelihood of dendritic action potential
initiation.
Given the possible implications of A-channel modulation listed above,
persistent downregulation of dendritic, transient K+
channels might also contribute to the long-lasting increase in neuronal
excitability observed after PKA and PKC activation (Malenka et al.,
1986; Hu et al., 1987; Storm, 1987; Hvalby et al., 1988; Heginbotham
and Dunwiddie, 1991; Slack and Pockett, 1991; Dunwiddie et al., 1992;
Pockett et al., 1993). Many of these effects, including enhancement of
EPSPs and increased probability of action potential firing, are similar
to those seen in LTP. These observations, along with occlusion
experiments and the fact that both PKC and PKA levels increase as a
result of the high-frequency stimulation used to induce LTP, strongly
suggest that both kinases play important roles in LTP (Malenka et al.,
1986; Malinow et al., 1989; Matthies et al., 1991; Wang and Feng, 1992;
Klann et al., 1993; Roberson and Sweatt, 1996). Recently, it has been
reported that genetic downregulation of PKA results in a decrease in
LTP, along with long-term memory deficits (Abel et al., 1997). Also,
dopamine acting via the D1/D5 receptor has been shown to increase the
magnitude of LTP and to inhibit depotentiation via a cAMP-dependent
mechanism (Otmakhova and Lisman, 1996, 1998). The transient
K+ channels, as substrates for PKA and PKC, may then
play a role in the induction and/or the expression of LTP. An
additional association between A-channels and LTP comes from studies
involving the mitogen-activated protein kinase (MAPK). Transient
K+ channels recorded in CA1 dendrites were found to
have their activation curve shifted to the left after blockade of MAPK
activation, and Kv4.2 was shown to be phosphorylated by MAPK (Adams et
al., 1997) (J. P. Adams, A. E. Anderson, D. A. Hoffman, J. D. English,
R. G. Cook, D. Johnston, P. Pfaffinger, J. D. Sweatt, unpublished observations). Other studies show that blocking MAPK activation severely reduces LTP induction in the hippocampus and facilitation in
Aplysia (English and Sweatt, 1996, 1997; Bailey et al.,
1997; Martin et al., 1997).
The downregulation of transient K+ channels in CA1
hippocampal dendrites by activators of PKA and PKC reported here is one of several demonstrations of A-channel modulation. A-type
K+ channels are modulated or blocked by
neurotransmitters, including serotonin, glutamate, and GABA, by cation
concentrations, by auxiliary subunits, by  -amyloid peptide, by
arachidonic acid, and by oxidative states (Rudy, 1988; Saint et al.,
1990; Chen and Wong, 1991; Wang et al., 1992; Covarrubias et al., 1994;
Rettig et al., 1994; Serôdio et al., 1994; Talukder and Harrison,
1995; Good et al., 1996; Keros and McBain, 1997). The vast number and
diversity of agents that modulate these channels suggest that they are
highly regulated and thus able to finely, dynamically, and selectively
control signals as they propagate through the dendrites.
| |
FOOTNOTES |
Received Dec. 22, 1997; revised Feb. 18, 1998; accepted Feb. 25, 1998.
This work was supported by National Institutes of Health Grants
NS11535, MH44754, and MH48432, and by Human Frontiers Science Program.
We thank Jeff Magee and Rick Gray for comments on this manuscript.
Correspondence should be addressed to Dr. Dan Johnston, Division of
Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX
77030.
| |
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Top
Abstract
Introduction
