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Previous Article | Next Article
Volume 17, Number 21, Issue of November 1, 1997 pp. 8147-8155
Copyright ©1997 Society for NeuroscienceBidirectional Regulation of DARPP-32 Phosphorylation by Dopamine
Akinori Nishi, Gretchen L. Snyder, and Paul Greengard Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021
ABSTRACT
Dopamine has been shown to stimulate phosphorylation of DARPP-32, a phosphoprotein highly enriched in medium-sized spiny neurons of the neostriatum. Here, we investigated the contribution of D1-like and D2-like dopamine receptors in the regulation of DARPP-32 phosphorylation in mouse striatal slices. D1-like and D2-like receptors had opposing effects on the state of DARPP-32 phosphorylation. The D1 receptor agonist SKF82526 increased DARPP-32 phosphorylation. In contrast, the D2 receptor agonist quinpirole decreased basal as well as D1 agonist-, forskolin-, and 8-bromo-cAMP-stimulated phosphorylation of DARPP-32. The ability of quinpirole to decrease D1-stimulated DARPP-32 phosphorylation was calcium-dependent and was blocked by the calcineurin inhibitor cyclosporin A, suggesting that the D2 effect involved an increase in intracellular calcium and activation of calcineurin. In support of this interpretation, Ca2+-free/EGTA medium induced a greater than 60-fold increase in DARPP-32 phosphorylation and abolished the ability of quinpirole to dephosphorylate DARPP-32. The antipsychotic drug raclopride, a selective D2 receptor antagonist, increased phosphorylation of DARPP-32 under basal conditions and in D2 agonist-treated slices. The results of this study demonstrate that dopamine exerts a bidirectional control on the state of phosphorylation of DARPP-32.
Key words: DARPP-32; dopamine; D2 receptor; phosphorylation; neostriatum; calcineurin; raclopride
INTRODUCTION
DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32,000, is a cytosolic protein that is selectively enriched in medium-sized spiny neurons in neostriatum (Ouimet et al., 1984
; Walaas and Greengard, 1984
Medium-sized spiny neurons of the neostriatum and nucleus accumbens receive dopaminergic input from cell bodies in the midbrain (Anden et al., 1964
There is considerable evidence for either synergistic or opposing interactions of D1- and D2-like dopamine receptors at the biochemical, physiological, and behavioral level (for review, see Jackson and Westlind-Danielsson, 1994
The aim of the present study was to determine the relative contribution of D1- and D2-like dopamine receptors to dopamine signaling through the DARPP-32/protein phosphatase-1 cascade, the possible biochemical pathways involved, and the possible effect on this signaling cascade of a widely used antipsychotic drug, raclopride.
MATERIALS AND METHODS
Preparation and incubation of striatal slices. Male C57BL/6 mice (5-8 weeks old) were decapitated. The brains were removed rapidly and placed in ice-cold, oxygenated Krebs-HCO3buffer (124 mM NaCl, 4 mM KCl, 26 mM NaHCO3, 1.5 mM CaCl2, 1.25 mM KH2PO4, 1.5 mM MgSO4, and 10 mM D-glucose, pH 7.4). Coronal slices (350 µm) were prepared using a vibratome. Striatum and nucleus accumbens were dissected from the slices in ice-cold Krebs-HCO3
80°C until assayed.
Immunoblotting. Frozen tissue samples were sonicated in boiling 1% SDS and boiled for an additional 10 min. Small aliquots of the homogenate were retained for protein determination by the BCA protein assay method (Pierce, Rockford, IL) using bovine serum albumin as a standard. Equal amounts of protein (100 µg) were loaded onto 12% acrylamide gels, and the proteins were separated by SDS-PAGE and transferred to nitrocellulose membranes (0.2 µm) (Schleicher & Schuell, Keene, NH) by the method of Towbin et al. (1979)
Antibody binding was revealed by incubation with goat anti-mouse horseradish peroxidase-linked IgG (1:6000-8000 dilution) (Pierce) and the ECL immunoblotting detection system (Amersham, Arlington Heights, IL). Chemiluminescence was detected by autoradiography using DuPont NEN autoradiography film, and phosphorylated (phospho-)DARPP-32 bands were quantified by densitometry using a Bio-Rad model 620 video densitometer and Bio-Rad 1-D Analyst software (Bio-Rad, Hercules, CA).
Data were analyzed by Student's t test with significance defined as p < 0.05.
RESULTS
Effect of dopamine on the level of phospho-DARPP-32
Dopamine has been shown to increase the state of phosphorylation of DARPP-32 in rat neostriatum (Walaas et al., 1983
Fig. 1. Effect of dopamine on the level of phospho-DARPP-32 in neostriatum. Slices were incubated with dopamine (100 µM) in the presence of the dopamine uptake inhibitor nomifensine (10 µM) for the indicated times. A, Phospho-DARPP-32 was detected at a molecular mass of ~32 kDa using mAb-23 against thr34-phospho-DARPP-32. Note that the phospho-DARPP-32 mAb also detected a cross-reactive protein band at a molecular mass of ~75 kDa, the levels of which were not affected by dopamine. B, Total DARPP-32 was detected in the same membrane as shown in A using mAb C24-5a against DARPP-32. C, The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with untreated tissue. Data represent mean ± SEM for the number of experiments shown in parentheses. * p < 0.05, ** p < 0.01 compared with 0 min;p < 0.05 compared with 2 min.
[View Larger Version of this Image (25K GIF file)]
The phosphorylation state-specific antibody for thr34-phospho-DARPP-32 also detects the thr35-phosphorylated form of inhibitor-1, a protein phosphatase-1 inhibitor that is closely related structurally and functionally to DARPP-32 (Aitkin et al., 1982 Effect of D1 and D2 agonists on the level of phospho-DARPP-32
Because both D1-like and D2-like dopamine receptors are expressed in neostriatum, the role of each of these dopamine receptor subclasses in the regulation of DARPP-32 phosphorylation was studied. The D1 agonist SKF82526 (1 µM) increased the level of phospho-DARPP-32 by 5.37 ± 0.99-fold (p < 0.01). DARPP-32 phosphorylation was maximal at 5-10 min of incubation, and the level of phosphorylation subsequently decreased (Fig. 2A). The effect of SKF82526 on DARPP-32 phosphorylation was dose-dependent with a half-maximal effect at ~100 nM and was abolished by the D1 antagonist SCH23390 (data not shown).
Fig. 2. Effects of D1 agonist (SKF82526) and D2 agonist (quinpirole) on the basal level of phospho-DARPP-32 in neostriatum. Slices were incubated with (A) SKF82526 (1 µM) or (B) quinpirole (1 µM) for the indicated times. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with untreated tissue. Data represent mean ± SEM for 4-12 experiments. * p < 0.05, ** p < 0.01 compared with 0 min;[View Larger Version of this Image (15K GIF file)]
Quinpirole (1 µM), a D2-like receptor agonist, decreased both the basal level (Fig. 2B) and the SKF82526-stimulated level (Fig. 3) of phospho-DARPP-32. The effect of quinpirole on the basal level was observed within 1 min of incubation and was sustained for at least 15 min (Fig. 2B). SKF82526 alone increased the level of phospho-DARPP-32 by 9.36 ± 2.06-fold in this series of experiments, and quinpirole at a concentration of 10 nM to 1 µM significantly reduced the SKF82526-stimulated DARPP-32 phosphorylation (Fig. 3). A near-maximal effect of quinpirole was observed at a concentration of 100 nM, at which concentration phospho-DARPP-32 decreased to ~60% of the SKF82526-stimulated level. These results clearly indicate that drugs which activate D1- and D2-like dopamine receptors have opposing effects on the state of phosphorylation of DARPP-32. 
Fig. 3. Opposing effects of D1 agonist (SKF82526) and D2 agonist (quinpirole) on the level of phospho-DARPP-32 in neostriatum. Slices were preincubated with the indicated concentrations of quinpirole (1 nM to 1 µM) for 5 min and then incubated with quinpirole plus SKF82526 (1 µM) for an additional 5 min. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with SKF82526 alone. Data represent mean ± SEM for four to five experiments. * p < 0.01 compared with SKF82526 alone.[View Larger Version of this Image (22K GIF file)]
Effect of the antipsychotic drug raclopride on the level of phospho-DARPP-32
Most antipsychotic drugs block D2-like dopamine receptors with potencies proportional to their clinical antipsychotic potencies. We examined whether the antipsychotic drug raclopride regulated DARPP-32 phosphorylation in neostriatal slices. Raclopride was chosen as the antipsychotic drug of choice because of its potent and selective interaction with D2-like receptors relative to D1-like receptors (Seeman and Van Tol, 1994
Fig. 4. Effect of the antipsychotic drug raclopride on the level of phospho-DARPP-32 in (A) neostriatum and (B) nucleus accumbens. Slices were incubated for a total of 20 min. Raclopride (1 µM) was added at 0 min, quinpirole (100 nM) at 10 min, and SKF82526 (1 µM) at 15 min of incubation. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with SKF82526 alone. A, Data represent mean ± SEM for six to nine experiments. * p < 0.01 compared with no addition;[View Larger Version of this Image (17K GIF file)]
Effects of SKF82526, quinpirole, and raclopride, similar to those seen in the neostriatum, were also observed in the nucleus accumbens (Fig. 4B). In the nucleus accumbens, SKF82526 increased the level of phospho-DARPP-32 (by about sevenfold), whereas quinpirole decreased the basal level of DARPP-32 phosphorylation (by ~50%). Quinpirole also decreased the SKF82526-stimulated DARPP-32 phosphorylation by ~60%. Raclopride alone induced a small increase in the basal level of phospho-DARPP-32. In addition, raclopride abolished the quinpirole-induced decrease in basal DARPP-32 phosphorylation as well as the quinpirole-induced decrease in SKF82526-stimulated DARPP-32 phosphorylation. Effect of D2 agonist on stimulated levels of phospho-DARPP-32
The ability of the D2 agonist quinpirole to reduce the basal and D1 agonist-stimulated levels of phospho-DARPP-32 could be explained in at least two ways (see Fig. 8). Because the activation of D2-like dopamine receptors has been reported to inhibit adenylyl cyclase through a Gi-mediated mechanism, it is possible that D2 receptor agonists decrease DARPP-32 phosphorylation by inhibiting D1 receptor-mediated increases in cAMP formation. Alternatively, activation of D2-like dopamine receptors might increase the activity of calcineurin, a calcium/calmodulin-dependent protein phosphatase, which has been shown to dephosphorylate phospho-DARPP-32 (King et al., 1984
Fig. 8. Postulated pathways by which dopamine may regulate DARPP-32 phosphorylation. Activation of D1 receptors increases cAMP, leading to the activation of PKA and the phosphorylation of DARPP-32 on thr34, converting it into a potent inhibitor of protein phosphatase-1. Activation of D2 receptors decreases DARPP-32 phosphorylation by two mechanisms (which might occur in the same or in different groups of neurons): one involves an inhibition of adenylyl cyclase, a decrease in cAMP, a decrease in activity of PKA and a decreased phosphorylation of DARPP-32; the other involves an increase in intracellular Ca2+, an activation of calcineurin, and an increased dephosphorylation of thr34-phospho-DARPP-32. This scheme is supported by evidence showing that NMDA receptor activation (Halpain et al., 1990[View Larger Version of this Image (17K GIF file)]
Fig. 5. Effect of D2 agonist (quinpirole) on stimulated levels of phospho-DARPP-32 in neostriatum. Slices were preincubated with quinpirole (1 µM) for 5 min and then incubated with quinpirole plus either (A) SKF82526 (1 µM), (B) forskolin (10 µM), or (C) 8-bromo-cAMP (1 mM) for an additional 5 min. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with SKF82526, forskolin, or 8-bromo-cAMP alone. Data represent mean ± SEM for three to four experiments. * p < 0.01 compared with SKF82526, forskolin, or 8-bromo-cAMP alone.[View Larger Version of this Image (13K GIF file)]
Effect of Ca-free/EGTA medium on the level of phospho-DARPP-32
We next determined whether the regulation of DARPP-32 phosphorylation by quinpirole was Ca2+-dependent. Incubation of slices in Ca2+-free/EGTA medium for 20 min increased the level of phospho-DARPP-32 by 61.8 ± 10.7-fold (Fig. 6). The effect of Ca2+-free/EGTA medium was much larger than the effect of forskolin or 8-bromo-cAMP. When Ca2+-free/EGTA medium was replaced by normal Krebs-HCO3
Fig. 6. Effect of Ca2+-free/EGTA medium on the level of phospho-DARPP-32 in neostriatum. Slices were incubated in control or Ca2+-free/EGTA medium for 20 min. A, Phospho-DARPP-32 was detected using a phosphorylation state-specific mAb (mAb-23). B, The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with control. Data represent mean ± SEM for four experiments. * p < 0.01 compared with control.[View Larger Version of this Image (24K GIF file)]
Under Ca2+-free conditions (Fig. 7), SKF82526, forskolin, and 8-bromo-cAMP each increased the level of phospho-DARPP-32, over the already high basal levels, by 1.55 ± 0.12-, 2.04 ± 0.22-, and 2.42 ± 0.53-fold, respectively. Under each of these conditions, quinpirole failed to decrease the level of phospho-DARPP-32. These results further suggest that the effect of D2-like receptor activation is mediated in a Ca2+-dependent manner. 
Fig. 7. Absence of effect of D2 agonist (quinpirole) on the level of phospho-DARPP-32 in Ca2+-free/EGTA medium. Neostriatal slices were incubated in Ca2+-free/EGTA medium for a total of 20 min. Buffer was replaced by Ca2+-free/EGTA medium at 0 min, quinpirole (1 µM) was added at 10 min, and (A) SKF82526 (1 mM), (B) forskolin (10 µM), or (C) 8-bromo-cAMP (1 mM) was added at 15 min of incubation. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with SKF82526, forskolin, or 8-bromo-cAMP alone. Data represent mean ± SEM for three to four experiments.[View Larger Version of this Image (15K GIF file)]
The possible involvement of the calcium/calcineurin pathway in the regulation of DARPP-32 phosphorylation was further examined by the use of thapsigargin, which increases intracellular Ca2+ levels by inhibition of endoplasmic reticulum Ca2+-ATPase (Thastrup et al., 1990 Effect of cyclosporin A on the level of phospho-DARPP-32
The effect of cyclosporin A, a specific inhibitor of calcineurin, on the level of phospho-DARPP-32 is shown in Table 1. Basal levels of phospho-DARPP-32 were increased 11- to 16-fold by cyclosporin A. Moreover, this calcineurin inhibitor acted synergistically with SKF82526 to increase the level of phospho-DARPP-32 and prevented the decrease that occurred after prolonged incubation of slices with the D1 agonist alone (Table 1A). Although cyclosporin A increased the basal level of phospho-DARPP-32 dramatically, a quinpirole-induced decrease in the level of phospho-DARPP-32 was still observed in its presence (Table 1B). These results suggest that a D2 agonist-induced decrease in the low, basal level of cAMP contributes to the ability of quinpirole to reduce DARPP-32 phosphorylation. In contrast, cyclosporin A abolished the ability of quinpirole to decrease the SKF82526-stimulated phosphorylation of DARPP-32 (Table 1C). These results indicate that when calcineurin is inhibited in the presence of SKF82526, quinpirole does not reduce the level of cAMP below that sufficient for optimal phosphorylation of DARPP-32.
Table 1. Effect of cyclosporin A on the level of phospho-DARPP-32 in neostriatum
Cyclosporin A ( Cyclosporin A (+) A. D1 agonist SKF82526 0 min 1.00 16.0 ± 1.6* 5 min 7.14 ± 0.97* 31.6 ± 2.8** 30 min 3.07 ± 0.66*,*** 28.0 ± 3.1** B. D2 agonist quinpirole 0 min 1.00 13.50 ± 1.74* 2 min 0.525 ± 0.051* 5.98 ± 1.28** 10 min 0.580 ± 0.058* 5.60 ± 1.05** C. D1 + D2 agonist Control 1.00 11.0 ± 2.5* SKF82526 10.61 ± 2.28* 21.1 ± 2.3** SKF82526 + quinpirole 4.78 ± 1.20*,*** 20.3 ± 2.5** Slices were preincubated in the absence or presence of cyclosporin A (CyA) (5 µM) for 60 min, followed by the addition of SKF82526 and/or quinpirole. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with control. A, Slices were incubated with SKF82526 (1 µM) for the indicated times. Data represent means ± SEM for five to nine experiments. * p < 0.01 compared with 0 min/CyA ( Effect of D2 agonist on the level of phospho-DARPP-32 is not mediated through the NMDA receptor
The activation of NMDA receptors decreases the phosphorylation of DARPP-32 in the neostriatum (Halpain et al., 1990
Table 2. Effect of D2 agonist on the level of phospho-DARPP-32 is not mediated through the NMDA receptor
MK801 ( MK801 (+) Control 0.103 ± 0.021* 0.247 ± 0.044** SKF82526 1.000 1.115 ± 0.078 SKF82526 + NMDA 0.042 ± 0.009* 1.042 ± 0.085 SKF82526 + quinpirole 0.598 ± 0.137* 0.616 ± 0.084*** Neostriatal slices were incubated for a total of 20 min in the absence or presence of the NMDA receptor antagonist MK801 (100 µM). MK801 was added at 0 min, NMDA (100 µM) or quinpirole (1 µM) at 10 min, and SKF82526 (1 µM) at 15 min of incubation. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with SKF82526 alone. Data represent means ± SEM for four to seven experiments. * p < 0.01 compared with SKF82526/MK801 ( Effect of D2 agonist on the level of phospho-DARPP-32 is not reduced by tetrodotoxin (TTX)
It seemed possible that the D2-mediated decrease in DARPP-32 phosphorylation might involve release of a neurotransmitter from neurons other than those containing D1 receptors. Therefore, we tested the effect of TTX, an inhibitor of sodium-dependent action potentials, on the ability of quinpirole to affect DARPP-32 phosphorylation. TTX failed to reduce the effect of quinpirole (Table 3). TTX increased the levels of phospho-DARPP-32 under basal conditions or in the presence of SKF82526. The effect of TTX, like that of MK-801, supports the possibility that in our preparation the NMDA receptor is tonically active and dephosphorylates DARPP-32 through activation of calcineurin. The data provide no support for the possibility that quinpirole achieved its effect by release of a neurotransmitter from interneurons.
Table 3. Effect of D2 agonist on the level of phospho-DARPP-32 is not reduced by tetrodotoxin (TTX)
TTX ( TTX (+) Control 0.686 ± 0.109 1.000* SKF82526 3.282 ± 0.575** 5.492 ± 0.780***,**** SKF82526 + quinpirole 1.716 ± 0.409*,*** 1.968 ± 0.559****, * Neostriatal slices were incubated for a total of 20 min in the absence or presence of TTX (1 µM). TTX was added at 0 min, quinpirole (1 µM) at 10 min, and SKF82526 (1 µM) at 15 min of incubation. The amount of phospho-DARPP-32 was quantitated by densitometry, and the data were normalized to values obtained with TTX alone. Data represent means ± SEM for six to seven experiments. ** p < 0.01, * p < 0.05 compared with control/TTX (
DISCUSSION
The results of this study demonstrate that DARPP-32 phosphorylation is regulated in mouse neostriatum through the opposing actions of D1- and D2-like dopamine receptors. Previous reports from this laboratory (Walaas et al., 1983
Adenylyl cyclase activity in the neostriatum is regulated through the opposing interactions of D1 and D2 receptors (Stoof and Kebabian, 1981
One such mechanism by which quinpirole may reduce the phosphorylation of DARPP-32 is through an increase in the activity of a protein phosphatase(s) that dephosphorylates thr34 on DARPP-32. The calcium/calmodulin-dependent protein phosphatase calcineurin has been shown to dephosphorylate DARPP-32 with a high efficiency in vitro (King et al., 1984
Calcium omission induced a dramatic increase in the level of phospho-DARPP-32 in neostriatal slices and blocked D2-mediated inhibition of DARPP-32 phosphorylation, further supporting a role for the calcium-dependent phosphatase in DARPP-32 regulation. Calcium omission increased DARPP-32 phosphorylation much more than did cyclosporin A treatment. This difference in effectiveness might be attributable to incomplete inhibition of calcineurin by cyclosporin A. Alternatively, other calcium-dependent processes could also contribute to the regulation of DARPP-32 phosphorylation. For instance, a major subtype of adenylyl cyclase, type V calcium-inhibitable adenylyl cyclase, is enriched in neostriatum (Cooper et al., 1995
Recent studies have shown that multiple effectors, including potassium channels, calcium channels, and phospholipase C, can be regulated by G-protein-mediated interactions with D2 receptors (Huff, 1996
In principle, the effect of D2 agonists in causing the dephosphorylation of DARPP-32 might be attributable either to a direct effect on D1 receptor-containing neurons or to an indirect effect involving release of neurotransmitter from other neurons. In support of a direct action, Surmeier et al. (1996)
Some groups have reported a very low degree of overlap of the two receptor classes (Gerfen et al., 1990
It is widely believed that a relative hyperactivity within mesolimbic and/or nigrostriatal dopaminergic systems contributes to the etiology of schizophrenia (Davis et al., 1991
The notion that the action of antipsychotic drugs might be mediated through increasing DARPP-32 phosphorylation is made more interesting by a recent report showing that treatment with a D1 antagonist (SCH39166) does not improve but actually worsens the symptoms of schizophrenia (Karlsson et al., 1995
FOOTNOTES
Received May 27, 1997; revised July 18, 1997; accepted Aug. 13, 1997.
This research was supported by Grant MH40899 from the United States Public Health Service (P.G.). The authors thank Drs. Angus C. Nairn and Gilberto Fisone for helpful discussion. Cyclosporin A was kindly provided by Abbott Laboratories and SKF82526 by SK&F Laboratories.
Correspondence should be addressed to Dr. Paul Greengard, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021.
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