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The Journal of Neuroscience, December 15, 1998, 18(24):10304-10309
Protein Kinase A Activity May Kinetically Upregulate the Striatal
Transporter for Dopamine
Melissa
Batchelor1 and
James O.
Schenk1, 2, 3
Departments of 1 Chemistry and
2 Biochemistry and Biophysics, and 3 Programs
in Pharmacology/Toxicology and Neuroscience, Washington State
University, Pullman, Washington 99164
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ABSTRACT |
The neuronal dopamine transporter (DAT) plays a key role in
terminating dopaminergic chemical neurotransmission; thus, the study of
the regulation of DAT activity is important in defining parameters
relevant to the control of dopaminergic neurotransmission. Interpretation of the results from previous work of this laboratory suggests that occupation of presynaptic autoreceptors increases DAT
activity. Second messenger signaling related to kinetic upregulation of
DAT has not been examined previously. However, others have shown that
protein kinase C activity may downregulate DAT activity, whereas
protein kinase A has shown variable results. Herein it is shown that
protein kinase A activity mediates the kinetic upregulation of DAT.
Quinpirole increased DAT activity that was blocked by sulpiride and the
protein kinase A selective inhibitor H-89. Brief incubations with
forskolin and 8-bromo-cAMP (8-Br-cAMP) were found to stimulate striatal
DAT activity by increasing the Vmax of
transport without affecting the Km.
Exposures >15 min had no effect. The 8-Br-cAMP-stimulated increases in
DAT activity were blocked by pre-exposure to H-89. Thus, second
messenger signaling via the cAMP cascade may mediate kinetic
upregulation of DAT. Kinetic analyses of the results suggest that
either insertion of DAT into the membrane or activation of pre-existing
DAT within the membrane mediates the regulation.
Key words:
dopamine transporter; protein kinase A; rotating disk
electrode voltammetry; striatum; 8-Br-cAMP; forskolin; quinpirole; sulpiride; H-89; H-7; H-9
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INTRODUCTION |
It has been suggested in recent
reports that the activity of the transporter for dopamine (DAT) may be
regulated (for review, see Reith et al., 1997 ). Various stimuli have
been shown to produce changes in the kinetic activity of DAT including:
increases in DAT activity after receptor occupation of the presynaptic
receptors of the D2 type (Meiergerd et al., 1993; Cass and
Gerhardt, 1994); persistent kinetic changes after withdrawal from
treatments with cocaine (Yi and Johnson, 1990; Meiergerd et al.,
1994a,b; Meiergerd et al., 1997); and decreases and increases in DAT
activity by a variety of compounds involved in second messenger
signaling (Pierce and Kalivas, 1997; Reith et al., 1997; Zhu et al.,
1997). In addition, high and low responding animals in a behavioral
model exhibit differences in DAT activity (Hooks et al., 1994). The cloned rat and human DATs possess consensus sites for phosphorylation by cAMP-dependent protein kinases and by protein kinase C in the N- and
C-terminal domains and third extracellular loop (Giros and Caron,
1993). Most studies of the effects of second messenger systems on DAT
kinetic activity have focused on the effects of protein kinase C
activity on DAT activity by studying the intracellular accumulation of
[3H]dopamine in cell culture systems expressing
DAT and in synaptosomes (Huff et al., 1997; Vaughn et al., 1997; Zhang
et al., 1997; Zhu et al., 1997). The results suggest that stimulation
of protein kinase C downregulates the kinetic activity of DAT by
decreasing the Vmax of accumulation. Others have
reported that stimulation of protein kinase C activity increases
DAT-mediated release of dopamine (see Giambalvo, 1992; Kantor and
Gnegy, 1998 and references therein). A couple of reports suggesting
that calcium-calmodulin-dependent protein kinases may upregulate DAT
have appeared recently (Uchikawa et al., 1995; Pierce and Kalivas,
1997), and an earlier report has shown that the cAMP-dependent
protein kinase, protein kinase A, upregulates
[3H]dopamine accumulation by DAT (Kadawaki et al.,
1990). Other investigations report that this protein kinase failed to
affect DAT activity (Tian et al., 1994; Copeland et al., 1996; Zhu et al., 1997). Because DAT can be upregulated by a variety of stimuli, and
others have shown kinetic upregulation of DAT by protein kinase A, we
examine this issue further. Herein we describe results of studies of
the effects of protein kinase A on the kinetically resolved inwardly
directed activity of striatal DAT as measured by rotating disk
electrode voltammetry. Because this approach monitors the clearance of
extracellular concentrations of dopamine ([DA]o),
it provides a window for observing what presynaptic and postsynaptic
receptors may "see" after alterations in DAT kinetic activity and a
much shorter window of observation of the kinetic activity of DAT than
traditional assays with [3H]dopamine. As will be
shown, it was found that protein kinase A activity transiently
upregulates DAT activity. Kinetic analyses suggest that insertion of
DAT into the neuronal membrane or activation of previously inactive DAT
within the membrane likely mediates the kinetic upregulation.
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MATERIALS AND METHODS |
Rotating disk electrode (RDE) voltammetric monitoring of the
velocity of the transporter for dopamine into striatal suspensions in
500 µl of physiological buffer were conducted as previously described
(Meiergerd and Schenk, 1995; Earles et al., 1998). Tissue suspensions
were prepared from striata obtained from rapid decapitation of male,
275-325 gm, Sprague Dawley rats. Rats were not pretreated with any
drug before experimentation, and the animal protocols used were
reviewed and approved by the University Animal Care and Use Committee.
The potentiostat was a Bioanalytical Systems Inc. (West Lafayette, IN)
model LC3D (Petite Ampére) with a time constant (5RC) changed
(details available on request) to 200 msec. The RDE controller and
glassy carbon electrode were purchased from Pine Instruments Inc.
(Grove City, PA), and the electroanalytical parameters used were:
Eapp = +450 mV versus Ag-AgCl and a rotation rate of 2000 rpm with current outputs fed to a Nicolet (Madison, WI) model 2090 digital oscilloscope.
The initial velocities of transport ( ) were defined and measured as
previously described (Meiergerd and Schenk, 1995), and values of
Km and Vmax were
estimated by fitting experimentally observed values of versus
[DA]o to the Michaelis-Menten expression using
commercially available nonlinear curve-fitting software (GraphPad
Prism, San Diego, CA). Indicators of the precision of the resulting
kinetic parameters are standard errors of regression (SER), and
statistical comparisons of the results were made using a z
test (Havlicek and Crain, 1988). More detailed analyses of changes observed in the kinetic parameters were based on treatments by
Fersht (1985) and Segel (1993).
All concentrations reported are final molarities in the incubation
chamber. Inhibition studies were conducted by pre-exposing the tissue
to an inhibitor dissolved in physiological buffer at a concentration
10-fold higher than its IC50. Exposure times were between
12 and 15 min. In experiments with 8-bromo-cAMP (8-Br-cAMP), 8-Br-cAMP
(50 µM) was added 1 min before dopamine. Forskolin and 1,9-dideoxyforskolin experiments were performed at 50 µM.
Stock concentrations of these agents were made in dimethylsulfoxide. The quinpirole experiments were conducted at 0.1 µM
quinpirole by adding it 30 sec before dopamine, as described previously
(Meiergerd et al., 1993). Sulpiride was added 5 min before dopamine.
Chemicals, solutions, and drugs. All solutions used in these
studies were made in university-supplied deionized water that was
purified further with a Nanopure (Barnstead, Dubuque, IA) water
purification system. The common buffer salts were purchased from Baker
Chemical Co. (Philipsburg, NJ). Forskolin, 1,9-dideoxyforskolin, dopamine (DA), 8-Br-cAMP, quinpirole (QUIN), sulpiride (SULP), 1-(5-isoquinolinesulfonyl)-2-methylpiperazine HCl (H-7), and
N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide HCl
(H-9) were purchased from Research Biochemicals (Natick, MA). Bisindolylmaleimides and
N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide HCl (H-89) were purchased from Calbiochem-Novabiochem (La Jolla, CA). A
bicarbonate-based physiological buffer at 37°C and pH 7.4 was used in
these experiments (composition in mM: 124 NaCl, 1.80 KCl,
1.24 KH2PO4, 1.30 MgSO4, 2.50 CaCl2·2H2O,
26.0 NaHCO3, and 10.0 glucose).
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RESULTS |
Figure 1 shows that 100 nM quinpirole increases the inwardly directed transport of
dopamine in striatal suspensions and that the increased velocity of
transport is blocked by 5 µM sulpiride and pre-exposure
to the nonselective protein kinase inhibitor H-9. H-89, a selective
inhibitor of protein kinase A, at 500 nM, also blocked the
effect of quinpirole. Thus, the effect of the cAMP pathway on DAT
activity was examined in more detail by measuring the kinetic
parameters of dopamine transport under different treatment conditions.
The control values of Km and
Vmax were found to be close to those reported
previously for this type of transport experiment (Meiergerd and Schenk,
1994; Wayment et al., 1998). The numerical results for the control
studies and other analyses estimated from data obtained under the other
treatment conditions along with the values of SER are listed in Table
1. In preliminary studies
(n  5) to set conditions for these experiments it was found that forskolin (at 50 µM) increased DAT activity at
4 µM dopamine from 793 ± 25 pmol · sec 1 · gm1
in controls to 903 ± 72 pmol · sec1 · gm1
after a 1 min incubation, whereas at a longer incubation time (15 min
as used by others in the study of protein kinase C effects, vide ante)
the transport value was lower at 786 ± 110 pmol · sec1 · gm1.
Values observed at 12 min of incubation were intermediate in value at
714 ± 99 pmol · sec1 · gm1.
Thus, the greatest numerical difference (the largest increased observed
velocity) with the best precision was observed at the 1 min incubation
time, and this condition was used throughout the remainder of the
study. Figure 2 shows that forskolin,
when compared with results obtained with the inactive forskolin
derivative 1,9-dideoxyforskolin increases the inwardly directed
transport of dopamine by increasing the Vmax of
transport. No statistically significant change in the
Km of the transport of dopamine was observed,
and the Vmax/Km
quotient was not different from controls (Table 1).
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Figure 1.
Upregulation of DAT activity by QUIN is blocked by
SULP and protein kinase inhibitors. The transport velocity of an
instantaneous pulse of 1.0 µM dopamine was measured. The
kinetic upregulation of striatal DAT activity by the dopamine agonist
QUIN (684 ± 70; n = 5) is reversed by the
dopamine antagonist SULP (428 ± 38; n = 6),
the nonselective protein kinase inhibitor H-9 (238 ± 18), and the
selective protein kinase A inhibitor H-89 (519 ± 36;
n = 15). The bars represent values
of SEM. The single asterisks indicate a difference from
the control at p  0.01, and the double
asterisks indicate a difference from QUIN at
p 0.01 via a z test. Each
n value represents a single experiment conducted with a
single striatum.
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Table 1.
Effects of agents modifying the activity of protein kinases
on kinetic parameters of the inwardly directed transport of dopamine
into striatal suspensions
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Figure 2.
The striatal transporter for dopamine is
kinetically upregulated by forskolin by increasing the
Vmax of transport. A shows
the Michaelis-Menten curves observed in the absence
(1,9-di-deoxyforskolin) and presence of forskolin. B
compares the value of Vmax in the presence
of forskolin (1152 ± 92 pmol · sec1 · gm1) to
that of 1,9-dideoxyforskolin (927 ± 54 pmol · sec1 · gm1).
The asterisk represents a difference from the control at
p 0.02 via a z test. Each point
represents n values of 9-23. Each n
value represents a single experiment conducted with a single
striatum.
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In preliminary experiments (n 3) to set conditions
for studies with 50 µM 8-Br-cAMP, it was found that DAT
activity at 1.0 µM dopamine was increased to 579 ± 41 pmol · sec1 · gm1
from the control value of 457 ± 35 pmol · sec1 · gm1.
However, when incubations with 8-Br-cAMP were conducted for 12 min
before adding dopamine, the observed velocity, 469 ± 27 pmol · sec1 · gm1,
was found to be statistically indistinguishable from the control value.
Thus, in subsequent experimentation 8-Br-cAMP was added 1 min before
dopamine. Figure 3 illustrates that
8-Br-cAMP kinetically upregulates the striatal transport of dopamine by
increasing the value of Vmax. No change in the
value of Km or the
Vmax/Km quotient was observed (Table 1). H-89 was also found to reverse the upregulation mediated by 8-Br-cAMP. Furthermore, it was found (Fig. 3) that H-89
alone reduced the velocity of the striatal transport of dopamine accompanied by a decrease in Vmax with no change
in Km (Table 1). When H-89 was used in the
presence of 8-Br-cAMP, the reduction in the kinetic parameters was
reversed and returned to control values. In contrast to the results
with the protein kinase A inhibitor, Figure
4 shows that bisindoylmaleimide I, an
inhibitor of protein kinase C, increased the transport velocity of the
striatal transport of dopamine. In these experiments a close to
saturating [dopamine] was used to provide results reflecting how the
Vmax of DAT activity may have changed. The
nonselective protein kinase inhibitors H-7 and H-9 reduced the values
of Vmax with no effect on
Km and the ratio,
Vmax/Km was
reduced relative to controls (Table 1).
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Figure 3.
Protein kinase A mediates a kinetic upregulation
of DAT. A shows Michaelis-Menten curves obtained in the
presence of 8-Br-cAMP alone and in the presence of 8-Br-cAMP and H-89.
Each point represents n values of 10-20. Each
n value represents a single experiment conducted with a
single striatum. B shows the effects of protein kinase A
on the Vmax of transport. The experimental
conditions and numerical results for the estimated
Vmax ± SER are (in
pmol · sec1 · gm1 wet
weight): control, 976 ± 67; 8-Br-cAMP, (50 µM, 1 min before DA) 1294 ± 83; H-89 (0.5 µM, exposure
~15 min before DA) plus 8-Br-cAMP (50 µM, 1 min before
DA), 1072 ± 53; and H-89, (0.5 µM, exposure ~15
min before DA) 777 ± 57. The error bars represent
the SER, and the single asterisks indicate differences
from controls at p 0.02 via a z
test. The double asterisks represent differences from
8-Br-cAMP at p 0.02 also via a z
test.
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Figure 4.
Protein kinase C and protein kinase A exhibit
opposing effects on the velocity of DAT. Bisindolylmaleimide I
(exposure 15 min), a protein kinase C inhibitor, produced an increase
in DAT activity. The results with H-89, a selective protein kinase A
inhibitor, were statistically lower than the controls under similar
experimental conditions. Each experiment was conducted by measuring the
transport velocity of an instantaneous pulse of 4.0 µM
dopamine, to estimate an effect on the value of
Vmax. The numerical values (in
pmol · sec1 · gm1 wet
weight) were: control, 796 ± 47, n = 23;
bisindolylmaleimide I, 983 ± 70, n = 7; and
H-89, 661 ± 17, n = 5. The
bars represent values of SER. The single
asterisks indicate a difference from the controls at
p 0.03 via a z test. The
n values represent a single experiment conducted with a
single striatum.
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DISCUSSION |
The findings of this study are that kinetic upregulation of DAT
results from activation of protein kinase A. Quinpirole, as in previous
studies (Meiergerd et al., 1993; Cass and Gerhardt, 1994), was found to
kinetically upregulate the transport of dopamine. The upregulation
could be blocked by sulpiride and the nonselective protein kinase
inhibitor H-9, as well as by the protein kinase A inhibitor H-89.
Further work showed that activation of adenylate cyclase with forskolin
or the addition of the membrane-soluble cAMP analog 8-Br-cAMP also
produced an H-89-sensitive kinetic upregulation of the striatal
transport of dopamine. H-89 alone was found to kinetically downregulate
the transport of dopamine, however, this effect could be modulated by
addition of 8-Br-cAMP. Taken together, these results suggest that a
cAMP-dependent protein kinase, protein kinase A, functions to
upregulate the striatal transporter for dopamine. The lack of effect on
the ratio,
Vmax/Km, is
taken as evidence that the kinetic upregulation is not the result of a
change in the kinetic state of DAT. However, this conclusion may be a
result of propagation of error in the analyses. The nonselective
inhibitors of protein kinases H-7 and H-9 reduced Vmax and the
Vmax/Km ratio,
suggesting that the downregulation observed was accompanied by a change
in the state DAT. When protein kinase C activity was inhibited
selectively the transport activity of DAT was found to increase, a
finding consistent with those previously reported for the effects of
altering protein kinase C activity on DAT activity (vide ante) in which
activation of protein kinase C resulted in a reduction of
Vmax.
Comments on the changes in DAT mediated by protein
kinase activity
An analysis of the observed kinetic results can suggest what
changes in interactions between dopamine and DAT occur as result of the
activity of protein kinases. The possibilities for a change in kinetic
activity include changes in Km,
Vmax, or both. The results obtained here
with protein kinase A indicate that only Vmax is
changed by the activity of the kinase. The significance of this change
can be examined in more detail. In treatments of Michaelis-Menten
kinetics the catalytic activity is depicted by the reaction
sequence:
where T signifies the transporter, DA signifies dopamine, DAT
signifies the dopamine-occupied transporter, k1
is the second order rate constant of association of DA with T,
k1 is the first order dissociation rate
constant of DA from DAT, and k2 is the first
order rate constant of the catalytic cycle of the transport of dopamine
across the membrane. In the classical kinetic treatment of this model
the interaction of DA with T is considered to be rapid and reversible,
and the transport event occurs as a second step signified by
k2 (Fersht, 1985). The well known steady state
analysis yields the Michaelis-Menten expression where
Km = [DA][T]/[DAT] = k1/k1, the
dissociation constant of DA from DAT
(KDA) and Vmax = k2 × the concentration (or density) of the
transporter. In the case in which k2 
k1 (the Briggs-Haldane kinetic condition) the
Km = KDA + k2/k1, the
Vmax has the same significance as before, and
the rate constants of association of DA with T should be in the
107-108 sec1
M1 range (Fersht, 1985).
Results of previous work by this laboratory (Meiergerd and Schenk,
1994; Meiergerd et al., 1994b) suggest that the kinetics of striatal
DAT follows the Briggs-Haldane model (Fersht, 1985; Segel, 1993)
because the second order rate constant of association of dopamine with
DAT was in the range indicated above for the Briggs-Haldane condition.
Indeed, similar conclusions from a different line of argument have been
made by Prof. Reith's laboratory (Zimanyi et al., 1989). Thus, if the
kinetics of transport are changed, but no change in the dissociation
constant occurs, then k2 should be the only
parameter changed, and both the values of Km and
Vmax should be altered by the change in kinetic
state. Alternatively, if the density of DAT is altered by a regulatory event but not the dissociation constant for dopamine, then a change in
Vmax would be the result with no change in the
Km. Finally, a change in
KDA as an effect would be reflected by a change
in Km only. Thus, in examining the values of the
kinetic parameters in Table 1, it can be hypothesized with reasonable
kinetic support that upregulation of DAT activity by forskolin and
8-Br-cAMP may be mediated by a change in the density of active DAT
because no change in Km was observed. In one
model in an expression system it has been shown that changes in
Vmax of human DAT result from activation of
previously inactive DAT within the membrane (Pristupa et al., 1998). In
the apparent downregulation of DAT activity by H-89, it may be
concluded that the density of active DAT within the membrane was
altered as well because there was a change (in the opposite direction)
involving Vmax only. These results suggest that
protein kinase A may mediate control of membrane trafficking of DAT or
activate otherwise inactive DAT within the membrane. In contrast to the
findings with inhibition of protein kinase A, it was observed that the
use of nonselective protein kinase inhibitors H-7 and H-9, presumably
inhibiting both protein kinase A and protein kinase C, results in a
diminution of Vmax as well as an increase in
Km, suggesting that binding of dopamine
to the transporter as well as a reduction in the density and/or the
value of k2 occurred.
Comparison to the findings of other investigators
These findings agree with those of Kadawaki et al. (1990),
Uchikawa et al. (1995), and Pierce and Kalivas (1997) in that protein kinase activity can kinetically upregulate DAT activity and appear to
contrast with those of some others investigating the effects protein
phosphorylation on the activity DAT (Tian et al., 1994; Copeland et
al., 1996; Zhu et al., 1997). These later investigators have focused on
the effects of protein kinase C activity on DAT activity. However,
those investigating the effects of protein kinase A within their
paradigms (i.e., incubation times, periods of monitoring effects, the
study of accumulation, etc.) used in the study of protein kinase C have
found no effects of forskolin and/or 8-Br-cAMP on DAT activity. We
observe here that the effects of these agents occur rapidly (within a
minute or so), and appear to be transient because the effect of DAT
activity is diminished or unobservable after ~12-15 min.
Furthermore, data consistent with others on effects of protein kinase C
activity were observed in the present study. The cited investigators
used paradigms outside the time window of 1 min used here for exposure
times to protein kinase A activators, and it may be assumed that the
results here are not in direct contrast with those of others; the
differences observed may simply be a consequence of the different time
windows of observation.
In conclusion, it is hypothesized that protein kinase A upregulates DAT
by increasing the density of active DAT within the membrane. These
results could be confirmed with binding experiments. However, binding
experiments are difficult to perform on very short time scales at the
present time. As studied by others and consistent with the data
presented here, protein kinase C has the opposite effect on DAT.
Combined, DAT may be regulated by protein kinase A in addition to
protein kinase C, but in apparent opposite directions. These two
phosphorylating systems are thought to act independently and, when
present simultaneously, not on the same substrate. Indeed, Vaughn et
al. (1997) have shown that 8-Br-cAMP and forskolin-stimulated protein
kinase A activity did not result in observable phosphorylation of DAT.
Taken together it may be assumed, as has been suggested by Reith et al.
(1997), that the substrates acted on by these two systems are different and that one, the protein kinase C system, may be involved in downregulating the activity of DAT via direct phosphorylation of DAT
protein. In contrast, the protein kinase A system may upregulate DAT
activity by phosphorylation of members of another biochemical control pathway.
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FOOTNOTES |
Received June 25, 1998; revised Sept. 29, 1998; accepted Sept. 30, 1998.
This work was supported by the State of Washington and grants from the
National Institute on Drug Abuse (NIDA) to J.O.S. (RO1 DA07384). J.O.S.
is a recipient of an NIDA Research Scientist Development Award (KO2
DA00184) and M.B. was supported by a fellowship from the Howard Hughes
Medical Institute.
Correspondence should be addressed to Dr. James O. Schenk, Department
of Chemistry, Washington State University, Pullman, WA 99164-4630.
Ms. Batchelor's present address: Department of Chemistry, University
of Michigan, Ann Arbor, MI.
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Top
Abstract
Introduction
