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The Journal of Neuroscience, December 15, 1998, 18(24):10297-10303
A Dopamine/D1 Receptor/Protein Kinase A/Dopamine- and
cAMP-Regulated Phosphoprotein (Mr 32 kDa)/Protein Phosphatase-1 Pathway Regulates Dephosphorylation
of the NMDA Receptor
Gretchen L.
Snyder1,
Allen A.
Fienberg1,
Richard
L.
Huganir2, and
Paul
Greengard1
1 Laboratory of Molecular and Cellular Neuroscience,
The Rockefeller University, New York, New York 10021, and
2 Department of Neuroscience, Howard Hughes Medical
Institute, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205
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ABSTRACT |
We have investigated the mechanism by which activation of dopamine
(DA) receptors regulates the glutamate sensitivity of medium spiny
neurons of the nucleus accumbens. Our results demonstrate that DA
regulates the phosphorylation state of the NR1 subunit of
NMDA-type glutamate receptors. The effect of DA was mimicked by
SKF82526, a D1-type DA receptor agonist, and by forskolin, an activator
of cAMP-dependent protein kinase (PKA), and was blocked by H-89, a PKA
inhibitor. These data indicate that DA increases NR1 phosphorylation
through a PKA-dependent pathway. DA-induced phosphorylation of NR1 was
blocked in mice bearing a targeted deletion of the gene for dopamine-
and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32), a phosphoprotein that is a potent and selective
inhibitor of protein phosphatase-1, indicating that the effect of PKA
is mediated, in part, by regulation of the DARPP-32/protein phosphatase-1 cascade. In support of this interpretation, NR1 phosphorylation was increased by calyculin A, a protein
phosphatase-1/2A inhibitor. A model is proposed in which the ability of
DA to regulate NMDA receptor sensitivity is attributable to a
synergistic action involving increased phosphorylation and decreased
dephosphorylation of the NR1 subunit of the NMDA receptor.
Key words:
D1 receptor; NMDA receptor; protein phosphatase-1; DARPP-32; protein kinase C; D2 receptor
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INTRODUCTION |
DARPP-32, a dopamine- and
cAMP-regulated phosphoprotein of Mr 32 kDa, is a
cytosolic protein that is selectively enriched in dopaminoceptive brain
neurons, including the medium spiny neurons of neostriatum and nucleus
accumbens (Walaas et al., 1983 ; Ouimet et al., 1984). Dopamine (DA), by
acting on the D1 class of DA receptors, stimulates adenylyl cyclase to
increase cAMP formation and the activity of cAMP-dependent protein
kinase (PKA), leading to the phosphorylation of DARPP-32 on a single
threonine residue, Thr34, converting it into a
potent inhibitor of protein phosphatase-1 (PP-1) (Hemmings et al.,
1984). Conversely, glutamate, by acting on NMDA receptors, increases
calcium influx and increases the activity of the
calcium/calmodulin-dependent protein phosphatase calcineurin, which
dephosphorylates DARPP-32, thereby inactivating it (King et al., 1984;
Nishi et al., 1997). The control of PP-1 activity by DARPP-32 is likely
to have a significant role in the regulation of neuronal excitability
(Fienberg et al., 1998). For example, the functions of calcium channels
(Surmeier et al., 1995), voltage-dependent sodium channels (Surmeier et
al., 1992; Schiffman et al., 1995), and
Na+,K+-ATPase (Aperia et al.,
1991) are regulated directly or indirectly by PP-1.
In mammals, D1 receptors enhance the currents evoked by NMDA agonists
(Cepeda et al., 1993; Harvey and Lacey, 1997; Hernandez-Lopez et al.,
1997; Cepeda and Levine, 1998). This effect of DA is mediated by a
PKA-dependent pathway (Colwell and Levine, 1995; Blank et al., 1997),
which most likely involves the phosphorylation and activation of
DARPP-32 (Blank et al., 1997). The mechanism by which the DA/D1
receptor/PKA/DARPP-32 pathway is able to control the activity of the
NMDA receptor has not been elucidated. However, NMDA receptors, which
are heteromeric complexes composed of two families of receptor subunits
NR1 and NR2, are substrates for phosphorylation by serine/threonine
protein kinases (Hollmann and Heinemann, 1992). In purified
systems, the NR1 subunit, which is required for a functional NMDA
receptor, is phosphorylated by PKA (Tingley et al., 1993; Leonard and
Hell, 1997). We report here that a DA/D1 receptor/PKA/DARPP-32/PP-1
pathway, by regulating the rate of dephosphorylation of NR1, provides
an additional and essential molecular mechanism for the control by DA
of NMDA receptor function in the nucleus accumbens.
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MATERIALS AND METHODS |
Preparation, radioactive labeling, and treatment of
nucleus accumbens slices. Male Sprague Dawley rats (150-200 gm)
were killed by decapitation. The brain was rapidly removed from the
skull and transferred to an ice-cold surface where it was blocked and then mounted to the cutting surface of a Vibratome (TPI). Coronal sections (500 µm) of the brain were cut and pooled in 10 ml of ice-cold, oxygenated phosphate-free Krebs' bicarbonate buffer containing the following components (in mM): 125 NaCl, 4 KCl, 26 NaHCO3, 1.5 CaCl2, 1.5 MgSO, and 10 glucose, pH 7.4. Slices of nucleus accumbens (Pellegrino
et al., 1979) were dissected from these coronal sections under a
dissecting microscope. The slices were pooled in a dish of cold buffer
and then transferred individually to 4 ml polypropylene centrifuge
tubes containing 2 ml of fresh buffer at 4°C. The Krebs' bicarbonate
buffer was then replaced with fresh solution. The tubes were connected
to an oxygenation manifold supplying a 95% O2/5%
CO2 mix and maintained in a 30°C water bath. After 15 min
the buffer was replaced with fresh, oxygenated Krebs' bicarbonate
buffer containing 2.0 mCi of [32P]orthophosphoric
acid (DuPont NEN, Boston, MA) (specific activity 8500-9120 Ci/mmol),
and the tissue was preincubated for 60 min. The radioactive buffer was
then removed, and tissue sections were rinsed twice with 2 ml of fresh
buffer. The tissue was incubated for 30 sec to 60 min in the absence or
presence of test substances, as indicated. At the end of the
incubation, the buffer was rapidly aspirated, and the tissue slices
were immediately frozen in liquid nitrogen and stored at  80°C until assayed.
In some experiments nucleus accumbens slices were prepared, as
described above for rat brain, from wild-type C57BL/6 mice (8-10 weeks
of age) and mice that lack the gene for DARPP-32 (Fienberg et al.,
1998). DARPP-32 mutant mice and their wild-type controls were generated
from the offspring of heterozygous mating pairs. All mice were
age-matched, and only males were used.
Immunoprecipitation and analysis of
[32P]phosphate-labeled NR1.
[32P]phosphate-labeled tissue slices were
sonicated in 150 µl of 1% SDS containing NaF (50 mM) and 1 mM EGTA added as phosphatase inhibitors, and a mixture of protease inhibitors, including 25 mM benzamidine, 100 µM phenylmethylsulfoxide,
20 µg/ml chymostatin, 20 µg/ml pepstatin A, 5 µg/ml leupeptin,
and 5 µg/ml antipain (Peptide International). To this homogenate was
added 5 vol of Buffer A, composed of 20 mM Tris/HCl, pH
8.0, 150 mM NaCl, 5 mM EDTA, 1% Triton X-100,
0.2% bovine serum albumin (BSA), and the mixture of phosphatase and
protease inhibitors described above. Aliquots of the homogenate (10 µl) were retained for the determination of total
[32P]phosphate incorporation into trichloroacetic
acid (TCA)-precipitated protein. A 10 mg aliquot of pre-swollen protein
A-Sepharose CL-4B (Pharmacia Biotech) was added to each sample, and the
mixture was agitated for 30 min at 4°C. The Sepharose beads were
pelleted by centrifugation for 15 sec at 2000 rpm in a tabletop
microcentrifuge. The supernatant was transferred to tubes containing 3 µg of a monoclonal antibody (54.1; PharMingen, San Diego, CA)
generated against the peptide sequence representing the intracellular
loop linking the putative transmembrane regions III and IV (amino acids 660-811) of the NMDA receptor subunit NR1. The samples were mixed for
2 hr at 4°C and then for an additional hour with 25 µl of a rabbit
anti-mouse antibody (1 mg/ml) (Organon Teknika Cappel, Durham,
NC). The homogenates were transferred to fresh 1.5 ml Eppendorf
tubes containing 10 mg of pre-swollen protein A-Sepharose CL-4B beads
and mixed for 1 hr at 4°C. The beads were pelleted by centrifugation
and washed once with 1 ml of Buffer A: three times with 1 ml of a
buffer containing 20 mM Tris/HCl, pH 8.0, 150 mM NaCl, 5 mM EDTA, 0.5% Triton X-100, 0.1%
SDS, and 0.2% BSA; three times with a buffer containing 20 mM Tris/HCl, pH 8.0, 500 mM NaCl, 0.5% Triton
X-100, and 0.2% BSA; and once with 1 ml of a buffer containing 50 mM Tris/HCl, pH 8.0. After the final wash the beads were
resuspended in 50 µl of a SDS-PAGE sample buffer composed of 50 mM Tris/HCl, pH 6.7, 10% glycerol, 2% SDS, 10%
2-mercaptoethanol, and 0.01% bromophenol blue. The tubes were vortexed
vigorously, and the beads were centrifuged. The recovered proteins were
separated on 7.5% acrylamide gels (Laemmli, 1970). The gels were
dried, and [32P]phosphate incorporation into NR1
was quantified using a PhosphorImager 400B and ImageQuant software from
Molecular Dynamics (Sunnyvale, CA). Values for
[32P]phosphate content were corrected for the
total [32P]phosphate incorporated into
TCA-precipitable protein.
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RESULTS |
Phosphorylation of NR1 in the nucleus accumbens by activators of
PKA and PKC
Immunoprecipitation of [32P]phosphate-labeled
protein from rat nucleus accumbens homogenates, using a monoclonal
antibody generated against NR1, yielded a single prominent protein band
on SDS-PAGE gels with an apparent Mr of 116 kDa.
A low level of basal phosphorylation was detected in untreated
[32P]phosphate-labeled slices. Forskolin, which by
activating adenylyl cyclase stimulates PKA, and phorbol
12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), each
increased the phosphorylation state of this protein band (Fig.
1). Results comparable to these were
obtained in experiments using rat neostriatal slices (data not
shown).
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Figure 1.
Effect of forskolin or PDBu on the phosphorylation
of the NR1 subunit of the NMDA receptor. Nucleus accumbens slices,
which had been prelabeled with [32P]phosphate for
60 min, were incubated for 5 min with various concentrations of either
forskolin (A) or PDBu (B).
Autoradiogram shows incorporation of
[32P]phosphate into NR1. Arrow
indicates the protein band corresponding to NR1.
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To verify the identity of the 116 kDa protein, nucleus accumbens slices
were treated with forskolin (10 µM) plus PDBu (5 µM). Immunoprecipitation of NR1 from these slices was
abolished by preadsorption of the NR1-specific monoclonal antibody with
10 µg/ml of a hexahistidine fusion protein containing the region between the third and fourth transmembrane domains of NR1 (residues 660-811) (data not shown).
Phosphorylation of NR1 by dopamine receptor agonists
Treatment of nucleus accumbens slices with DA (100 µM) in the presence of nomifensine (10 µM),
an inhibitor of DA reuptake, increased
[32P]phosphate content of immunoprecipitated NR1
(Fig. 2). The
[32P]phosphate content of NR1 was increased about
threefold within 1 min of DA addition. NR1 phosphorylation decreased to
near basal levels by 10 min of incubation.
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Figure 2.
Effect of DA on the phosphorylation of NR1.
Nucleus accumbens slices, which had been prelabeled with
[32P]phosphate for 60 min, were incubated for
0.5-10 min with dopamine (100 µM) plus nomifensine (10 µM), a dopamine uptake inhibitor.
[32P]phosphate incorporation into NR1 was
determined as described in Materials and Methods. The data were
calculated as percentage of radioactivity in control slices and
represent means ± SEM for five (0-5 min) or three (10 min)
experiments (different from control; *p < 0.05, **p < 0.01; Student's t
test).
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DA receptors have been divided into D1 and D2 subclasses (for review,
see Sibley and Monsma, 1992). SKF82526 (1 µM) (Fig. 3) and SKF81297 (1 µM)
(Table 1), agonists at D1-type DA
receptors, each increased [32P]phosphate
incorporation into NR1 by two- to fourfold within 5 min of incubation
and maintained phosphorylation of NR1 for at least 10 min. In contrast,
the D2-type receptor agonist quinpirole alone had no significant effect
on the state of phosphorylation of NR1 under the same conditions (Fig.
3).
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Figure 3.
Effect of D1-type and D2-type dopamine agonists on
the state of NR1 phosphorylation. Nucleus accumbens slices, which had
been prelabeled with [32P]phosphate for 60 min,
were incubated for 2.5-10 min with a D1 agonist (SKF82526, 1 µM) or a D2 agonist (quinpirole, 1 µM), as
shown in autoradiograms (A) and a bar graph
(B).
[32P]phosphate incorporation into NR1 was
determined as described in Materials and Methods. Data were calculated
as percentage of radioactivity in control slices and represent
means ± SEM for four experiments (different from control;
*p < 0.05, **p < 0.01;
Student's t test).
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Table 1.
Effects of D2 receptor agonist and D2 receptor antagonist
on D1-stimulated increase in NR1 phosphorylation in nucleus accumbens
slices
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Activation of D2-type DA receptors blocks D1-stimulated increases in
DARPP-32 phosphorylation both by reducing PKA-dependent phosphorylation
of DARPP-32 and by increasing dephosphorylation of DARPP-32 by
calcineurin (Nishi et al., 1997). We examined whether D2 receptor
activation would also modulate D1-stimulated phosphorylation of NR1.
The ability of the D1-type receptor agonist SKF81297 to increase the
phosphorylation of NR1 was abolished by the simultaneous presence of
quinpirole (Table 1).
We also examined whether raclopride, a potent neuroleptic drug, might
affect the phosphorylation state of NR1. Pretreatment of slices with
raclopride inhibited the ability of quinpirole to decrease
D1-stimulated NR1 phosphorylation (Table 1).
The effect of protein kinase inhibitors on DA-induced
NR1 phosphorylation
Selective protein kinase inhibitors were used to assess the
relative involvement of intracellular signaling pathways involving PKA
or PKC in the regulation by dopamine of the phosphorylation state of
NR1. Preincubation of nucleus accumbens slices with H-89, an inhibitor
of PKA (0.5 µM), had no significant effect on basal phosphorylation of NR1 but did abolish the increase in
[32P]phosphate content of NR1 induced by treatment
with dopamine (Table 2A). In contrast,
calphostin C (1 µM), an inhibitor of PKC, had no
significant effect on either the basal or the DA-stimulated phosphorylation of NR1 in nucleus accumbens slices (Table 2B). Under
these conditions, calphostin C treatment fully blocked phosphorylation of the receptor subunit in response to PDBu (5 µM) (Table
2C). These experiments indicate that the increase in
[32P]phosphate incorporation into NR1 induced by
DA treatment involves activation of PKA but not PKC.
The role of the DARPP-32/protein phosphatase-1 pathway in the
regulation of NR1 phosphorylation
It seemed possible that the ability of the DA/D1 receptor/PKA
pathway to increase the state of phosphorylation of NR1 might be
attributable to direct phosphorylation of NR1 by PKA and/or to a
decreased dephosphorylation of NR1 mediated by the PKA/DARPP-32/PP-1 pathway (see Fig. 7). One way to evaluate the potential role of the
DARPP-32/PP-1 pathway in the regulation of NR1 phosphorylation was to
examine the effects of protein phosphatase inhibitors on NR1
phosphorylation. Treatment of rat nucleus accumbens slices with
calyculin A, a potent PP-1/2A inhibitor, caused a severalfold increase
in NR1 phosphorylation (Fig. 4). These
experiments indicate a role for PP-1 or -2A in controlling the state of
phosphorylation of NR1 in the nucleus accumbens.
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Figure 4.
Effect of calyculin A, a protein phosphatase-1/2A
inhibitor, on the phosphorylation state of NR1. Nucleus accumbens
slices, which had been prelabeled with
[32P]phosphate, were incubated for 5-45 min in
the absence or presence of calyculin A (200 nM).
[32P]phosphate-labeled NR1 was analyzed as
described in Materials and Methods. Data were normalized to
radioactivity in slices incubated for 45 min with calyculin A and
represent means ± SEM for four experiments (different from
control; *p < 0.05; Mann-Whitney U
test). Incubation of slices in the absence of calyculin A for 45 min
had no effect on the amount of
[32P]phosphate-labeled NR1.
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Activation of calcineurin by calcium has been shown in purified systems
and in tissue slices to promote dephosphorylation and inactivation of
DARPP-32 (King et al., 1984; Halpain et al., 1990; Nishi et al., 1997).
As one way of evaluating the possible role of DARPP-32 in the
regulation of the state of phosphorylation of NR1, we tested the
ability of cyclosporin A, a potent inhibitor of calcineurin, to affect
NR1 phosphorylation. Pretreatment of slices with cyclosporin A blocked
the ability of D2 receptor activation to decrease the D1
receptor-stimulated phosphorylation of NR1 (Fig.
5), consistent with a role for DARPP-32
in the regulation of NR1 phosphorylation.
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Figure 5.
Effect of cyclosporin A, a calcineurin inhibitor,
on the phosphorylation state of NR1. Nucleus accumbens slices were
prelabeled with [32P]phosphate for 60 min. Slices
were incubated for a total of 60 min in the absence (control) or
presence of cyclosporin A (CSA) (5 µM). At
55 min, a D1 agonist (SKF81297, 1 µM) and/or or a D2
agonist (quinpirole, 1 µM) was added.
[32P]phosphate incorporation into NR1 was
determined as described in Materials and Methods. Data were calculated
as percentage of radioactivity in control slices and represent
means ± SEM for four experiments (different from
D1+D2 alone; *p < 0.05; Student's
t test). CSA had no effect on the SKF81297-stimulated
phosphorylation of NR1.
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To further evaluate the role of DARPP-32 in the regulation of NR1
phosphorylation, we examined the ability of the receptor to be
phosphorylated in mice bearing a targeted deletion of the gene for
DARPP-32. As in rat nucleus accumbens, a low level of basal
[32P]phosphate incorporation was observed in
untreated slices of mouse nucleus accumbens. Incubation with DA (100 µM) plus nomifensine (10 µM) for 1 min
induced approximately a three- to fourfold increase in
[32P]phosphate content of NR1 in accumbens slices
prepared from wild-type C57BL/6 mice (Fig.
6A). Phosphorylation of
the receptor increased to a maximal level within 1 min of DA treatment
and remained high for >5 min, gradually decreasing toward basal levels
after 10 min of drug exposure (data not shown). The DA-induced increase in NR1 phosphorylation was virtually abolished in nucleus accumbens slices from DARPP-32 mutant mice at 1 min (Fig. 6A)
as well as at 2 and 5 min (data not shown) of DA treatment.
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Figure 6.
Effect of genetic deletion of DARPP-32 on the
state of phosphorylation of NR1. Nucleus accumbens slices prepared from
wild-type and DARPP-32 mutant mice were prelabeled with
[32P]phosphate for 60 min and then incubated in
the absence or presence of DA (100 µM) plus nomifensine
(10 µM) for 1 min (A), forskolin (1 µM) for 5 min (B), or PDBu (5 µM) for 15 min (C).
[32P]phosphate incorporation into NR1 was
determined as described in Materials and Methods. Data were calculated
as percentage of radioactivity in control slices and represent
means ± SEM for three to six experiments (different from wild
type; * p < 0.05; Student's t
test).
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The inability of DA to stimulate phosphorylation of NR1 in mutant
tissue could not be accounted for by a decrease in the number or
sensitivity of D1 receptors, because the Bmax
and Kd for [3H]SCH23390
binding were unaffected by DARPP-32 mutation (P. Svenningsson, A. A. Fienberg, and B. Fredholm, unpublished observations). This difference in phosphorylation of NR1 was also not caused by differences in labeling efficiency between mutant and wild-type tissue slices, because the total [32P]phosphate incorporation
into protein, as measured by TCA-precipitable counts, was unaffected by
the DARPP-32 mutation (data not shown). The alterations in
DA-stimulated NR1 phosphorylation were not caused by a difference in
the total amount of receptor protein expressed in mutant tissue because
the levels of NR1 protein detected by immunoblotting were comparable in
wild-type and mutant mice. They were not caused by changes in the basal
level of phosphorylation of NR1 (data not shown). Finally, these
differences were not attributable to alterations in the level of PP-1
protein nor in the activity of either PKA or adenylyl cyclase in the
DARPP-32 mutant mice (Fienberg et al., 1998).
The phosphorylation of NR1 in response to application of DA was
compared with that observed in response to activation of either PKA by
forskolin or PKC by PDBu. Treatment of slices with forskolin (1 µM) for 5 min increased NR1 phosphorylation significantly
in tissue slices from wild-type mice but had a smaller effect on NR1
phosphorylation in slices from the DARPP-32 mutant mice (Fig. 6B). In contrast to the diminished increase in the
[32P]phosphate content of NR1 seen in mutant
tissue in response to DA or forskolin, PDBu treatment for 15 min
increased NR1 phosphorylation in both the wild-type and mutant tissue
by four- to fivefold (Fig. 6C).
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DISCUSSION |
The present results show that phosphorylation of the NMDA receptor
subunit NR1 is regulated by a DA/D1 receptor/PKA/DARPP-32/PP-1 cascade
in medium spiny neurons of the nucleus accumbens. Our data indicate
that activation of DA receptors increases the state of phosphorylation
of NR1 in these cells through a synergistic mechanism involving
increased phosphorylation and decreased dephosphorylation of the NR1
receptor (Fig. 7). These data are
consistent with evidence that NMDA receptor function is regulated by
protein kinases and protein phosphatases.
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Figure 7.
Proposed mechanism for regulation by dopamine of
the state of phosphorylation of NR1. In this model, dopamine, by
activation of D1-type DA receptors, increases adenylyl cyclase
activity, leading to formation of cAMP and activation of PKA. Activated
PKA phosphorylates both NR1 and DARPP-32. Phosphorylated DARPP-32
inhibits dephosphorylation of NR1 by PP-1. The activation of D2-type DA
receptors, which is blocked by raclopride, (1) inhibits cAMP formation,
leading to a decreased phosphorylation both of NR1 and of DARPP-32, and
(2) increases calcium-dependent activation of calcineurin (Nishi et
al., 1997), leading to increased dephosphorylation of DARPP-32.
D1-type, D1-type dopamine receptor;
D2-type, D2-type dopamine receptor; AC,
adenylyl cyclase; PKA, cAMP-dependent protein kinase;
DARPP-32, dopamine- and cAMP-regulated phosphoprotein of
Mr 32 kDa; PP-1, protein
phosphatase-1; NR1, NMDA receptor subunit NR1.
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The role of the DARPP-32/PP-1 cascade in regulating currents evoked by
NMDA agonists has been studied in homomeric NR1 subunits expressed in
Xenopus oocytes (Blank et al., 1997). In oocytes injected
with rat neostriatal poly(A+) mRNA, activation of
PKA by forskolin potentiated NMDA responses. Coinjection of oocytes
with neostriatal mRNA and antisense oligodeoxynucleotides directed
against DARPP-32 reduced the PKA enhancement of NMDA responses. NMDA
responses recorded from oocytes injected with rat hippocampal
poly(A+) mRNA were not affected by stimulation of
PKA, indicating that the amount of inhibitor-1, a compound similar in
structure and function to DARPP-32, which is present in hippocampus, is
not sufficiently abundant to mediate the effect of forskolin on NMDA responses. However, when oocytes were coinjected with hippocampal poly(A+) mRNA plus complementary RNA coding for
DARPP-32 (resulting in a greatly elevated level of this PP-1
inhibitor), NMDA responses were potentiated after stimulation with PKA.
These data suggest that the DARPP-32/PP-1 cascade plays a major role in
regulating responses to NMDA agonists and are supported by other
studies showing that drugs that inhibit the activity of PP-1/-2A also enhance NMDA responses in Xenopus oocytes (Blank et al.,
1997) and in neurons (Wang et al., 1994).
It is plausible to hypothesize that phosphorylation/dephosphorylation
of the NMDA receptor contributes to the mechanism by which activation
of DA receptors regulates the glutamate sensitivity of medium spiny
neurons. It seems likely that alterations in L-type calcium
conductances are also involved in the mechanism by which PKA pathways
involving DARPP-32 enhance currents evoked by NMDA agonists. It was
shown by Surmeier et al. (1995) that L-type calcium conductances were
increased by activation of a D1/PKA/PP-1/DARPP-32 cascade in medium
spiny neurons. Moreover, the D1 receptor-mediated enhancement of
NMDA-evoked currents in medium spiny neurons is dependent on
enhancement of L-type calcium conductances (Hernandez-Lopez et al.,
1997; Cepeda et al., 1998). Presumably, the NMDA-evoked currents
depolarized the dendrites leading to activation of L-type calcium
channels. According to this scenario, when calcium function was
enhanced by D1 receptor stimulation, the larger magnitude of the
depolarization was caused by activation of both NMDA receptors and
calcium channels.
Preliminary results using wild-type and DARPP-32 mutant mice and
phosphorylation state-specific antibodies against individual phosphorylation sites on NR1 indicate that the DA-mediated increases in
NR1 phosphorylation demonstrated in the present study occur at the PKA
site (serine897) and at a PKC-dependent
phosphorylation site (serine890) (Snyder et al.,
1998). These data imply that PKC-dependent phosphorylation sites that
are substrates for PP-1 can be regulated by DA through activation of a
D1 receptor/DARPP-32/PP-1 pathway.
The functional effect of phosphorylation of NR1 at the PKA-dependent
site at serine897 (Tingley et al., 1997) has yet to
be clarified. However, there is substantial evidence to indicate that
PKC-dependent phosphorylation enhances the conductance of native NMDA
receptors in spinal cord and hippocampal neurons (Chen and Huang, 1991,
1992). The specific role of NR1 phosphorylation in regulating various
properties of the NMDA receptor has been examined using NR1 subunits
expressed in fibroblasts. In these studies phosphorylation of NR1 by
PKC (at serine889 and serine890)
disrupted the subcellular distribution of NR1 protein, suggesting that
phosphorylation may play an important role in receptor clustering (Ehlers et al., 1995). Studies in HEK-293T cells indicate that calmodulin binds to sites in the COOH-terminal region of NR1 (Ehlers et
al., 1996; Hisatsune et al., 1997) and that calmodulin binding to NR1
results in a fourfold decrease in NMDA channel open probability (Ehlers
et al., 1996). PKC-dependent phosphorylation of NR1 (also in the
COOH-terminal region) inhibits calmodulin binding, suggesting a
possible role for NR1 phosphorylation in modulating the
Ca2+-dependent inactivation of the NMDA receptor
(Hisatsune et al., 1997).
D1 and D2 subclasses of DA receptors exerted opposing effects on the
phosphorylation state of NR1 in the nucleus accumbens. The activation
of D2 receptors blocked a D1 receptor-mediated increase in NR1
phosphorylation, an effect that was prevented by cyclosporin A, an
immunosuppressant drug that inhibits calcineurin (Fig. 7). These data
are consistent with a previous report showing that D2 agonists activate
calcineurin, leading to a decrease in the state of phosphorylation of
DARPP-32 in these neurons (Nishi et al., 1997). The precise mechanism
for the activation of calcineurin has not been elucidated. However,
because these experiments were performed in tissue slices, these
effects may involve activation of D2 receptors on medium spiny neurons
and/or activation of D2 receptors on terminals of afferent projections
to the nucleus accumbens (Nishi et al., 1997). The D2-mediated decrease
in NR1 phosphorylation was also blocked by raclopride, a neuroleptic drug that is a D2 receptor antagonist. These data imply that typical antipsychotic drugs, which like raclopride block the binding of DA to
D2 receptors, may achieve part of their clinical effect through the
regulation of DA-stimulated phosphorylation of NR1.
Certain of the behavioral and biochemical manifestations of drug
addiction have been attributed to interactions between D1-type dopamine
receptors and NMDA-type glutamate receptors in the nucleus accumbens
(Self and Nestler, 1995; for review, see Hyman, 1996; Koob and LeMoal,
1997). For example, the ability of amphetamine to induce behavioral
sensitization (Wolf and Jeziorski, 1993) and to increase the expression
of immediate early genes in rodents (Konradi et al., 1996) is dependent
on stimulation of both D1 and NMDA receptors. The precise nature of the
D1/NMDA interaction responsible for these effects is still not fully
understood. The results of the present study provide a molecular
mechanism by which the DA/D1 receptor pathway might interact with the
NMDA receptor to produce some of these observed responses.
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FOOTNOTES |
Received May 20, 1998; revised Sept. 11, 1998; accepted Sept. 30, 1998.
This work was supported by United States Public Health Service Grants
MH-40899 and DA-10044. We thank Drs. Angus Nairn and Irina Dulubova for
advice and comments on this manuscript, and Dr. Lit-Fui Lau (Johns
Hopkins University) for providing NR1 fusion protein used in the
preabsorption experiments. The excellent technical assistance of
Carmina Valle and Peter Ingrassia is gratefully acknowledged.
Correspondence should be addressed to Gretchen L. Snyder, The
Rockefeller University, Box 296, 1230 York Avenue, New York, NY 10021.
| |
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Top
Abstract
Introduction
