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  • 1
    Electronic Resource
    Electronic Resource
    Role of Calcineurin and Protein Phosphatase-2A in the Regulation of DARPP-32 Dephosphorylation in Neostriatal Neurons (1999)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 72 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cyclic AMP-dependent protein kinase, resulting in its conversion to a potent inhibitor of protein phosphatase-1 (PP-1). Conversely, Thr34-phosphorylated DARPP-32 is dephosphorylated and inactivated in vitro by calcineurin and protein phosphatase-2A (PP-2A). We have investigated the relative contributions of these protein phosphatases to the regulation of DARPP-32 dephosphorylation in mouse neostriatal slices. Cyclosporin A (5 μM), a calcineurin inhibitor, maximally increased the level of phosphorylated DARPP-32 by 17 ± 2-fold. Okadaic acid (1 μM), an inhibitor of PP-1 and PP-2A, had a smaller effect, increasing phospho-DARPP-32 by 5.1 ± 1.3-fold. The effect of okadaic acid on DARPP-32 phosphorylation was shown to be due to inhibition of PP-2A activity. Incubation of slices in the presence of cyclosporin A plus either okadaic acid or calyculin A, another PP-1/PP-2A inhibitor, caused a synergistic increase in the level of phosphorylated DARPP-32. The use of Ca2+-free/EGTA medium mimicked the effects of cyclosporin A on DARPP-32 phosphorylation, supporting the conclusion that the action of cyclosporin on DARPP-32 phosphorylation was attributable to blockade of the Ca2+-dependent activation of calcineurin. The results indicate that calcineurin and PP-2A, but not PP-1, act synergistically to maintain a low level of phosphorylated DARPP-32 in neostriatal slices.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0722015.x
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  • 2
    Electronic Resource
    Electronic Resource
    Regulation of Na+, K+ -ATPase Isoforms in Rat Neostriatum by Dopamine and Protein Kinase C (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : Our previous studies showed that dopamine inhibits Na+, K+ -ATPase activity in acutely dissociated neurons from striatum. In the present study, we have found that in this preparation, dopamine inhibited significantly (by ~25%) the activity of the α3 and/or α2 isoforms, but not the α1 isoform, of Na+, K+ -ATPase. Dopamine, via D1 receptors, activates cyclic AMP-dependent protein kinase (PKA) in striatal neurons. Dopamine is also known to activate the calcium- and phospholipid-dependent protein kinase (PKC) in a number of different cell types. The PKC activator phorbol 12,13-dibutyrate reduced the activity of Na+, K+ -ATPase α3 and/or α2 isoforms (by ~30%) as well as the α1 isoform (by ~15%). However, dopamine-mediated inhibition of Na+, K+ -ATPase activity was unaffected by calphostin C, a PKC inhibitor. Dopamine did not affect the phosphorylation of Na+, K+ -ATPase isoforms at the PKA-dependent phosphorylation site. Phorbol ester treatment did not alter the phosphorylation of α2 or α3 isoforms of Na+, K+ -ATPase in neostriatal neurons but did increase the phosphorylation of the α1 isoform. Thus, in rat neostriatal neurons, treatment with either dopamine or PKC activators results in inhibition of the activity of specific (α3 and/or α2) isoforms of Na+, K+ -ATPase, but this is not apparently mediated through direct phosphorylation of the enzyme. In addition, PKC is unlikely to mediate inhibition of rat Na+, K+ -ATPase activity by dopamine in neostriatal neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0731492.x
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  • 3
    Electronic Resource
    Electronic Resource
    Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 87 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Methylphenidate (MPH), a dopamine uptake inhibitor, is the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children. We examined the effect of MPH on dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) phosphorylation at Thr34 (PKA-site) and Thr75 (Cdk5-site) using neostriatal slices from young (14–15- and 21–22-day-old) and adult (6–8-week-old) mice. MPH increased DARPP-32 Thr34 phosphorylation and decreased Thr75 phosphorylation in slices from adult mice. The effect of MPH was blocked by a dopamine D1 antagonist, SCH23390. In slices from young mice, MPH did not affect DARPP-32 phosphorylation. As with MPH, cocaine stimulated DARPP-32 Thr34 phosphorylation in slices from adult, but not from young mice. In contrast, a dopamine D1 agonist, SKF81297, regulated DARPP-32 phosphorylation comparably in slices from young and adult mice, as did methamphetamine, a dopamine releaser. The results suggest that dopamine synthesis and the dopamine transporter are functional at dopaminergic terminals in young mice. In contrast, the lack of effect of MPH in young mice is likely attributable to immature development of the machinery that regulates vesicular dopamine release.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.02101.x
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  • 4
    Electronic Resource
    Electronic Resource
    Regulation of spinophilin Ser94 phosphorylation in neostriatal neurons involves both DARPP-32-dependent and independent pathways (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 95 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Spinophilin is a protein phosphatase-1 (PP-1)- and actin-binding protein that is enriched in dendritic spines. Phosphorylation of the actin-binding domain of rat spinophilin at one or more sites by protein kinase A (PKA) inhibits actin binding. Here, we investigated the regulation of mouse spinophilin that contains only a single PKA-site (Ser94) within its actin-binding domain. In vitro phosphorylation of Ser94 resulted in the dissociation of spinophilin from actin filaments. In mouse neostriatal slices, phospho-Ser94 (p-Ser94) was dephosphorylated mainly by PP-1 and also by PP-2A. Activation of dopamine D1 receptors in striatonigral medium spiny neurons, and of adenosine A2A receptors in striatopallidal medium spiny neurons increased, whereas activation of dopamine D2 receptors in striatopallidal neurons decreased, spinophilin Ser94 phosphorylation. In neostriatal slices from DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) knockout mice, the effects of D1, D2 and A2A receptors were largely attenuated. Activation of NMDA receptors decreased Ser94 phosphorylation in a PP-2A-dependent, but DARPP-32-independent, manner. These results suggest that PKA-dependent phosphorylation of spinophilin at Ser94 in both striatonigral and striatopallidal neurons requires synergistic contributions from the PKA and DARPP-32/PP-1 pathways. In addition, PP-2A plays a role in Ser94 dephosphorylation in response to activation of both D2 and NMDA receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03491.x
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  • 5
    Electronic Resource
    Electronic Resource
    Identification of tyrosine hydroxylase as a physiological substrate for Cdk5 (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 91 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cyclin-dependent kinase 5 (Cdk5) is emerging as a neuronal protein kinase involved in multiple aspects of neurotransmission in both post- and presynaptic compartments. Within the reward/motor circuitry of the basal ganglia, Cdk5 regulates dopamine neurotransmission via phosphorylation of the postsynaptic signal transduction pathway integrator, DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32 000). Cdk5 has also been implicated in regulating various steps in the presynaptic vesicle cycle. Here we report that Cdk5 phosphorylates tyrosine hydroxylase (TH), the key enzyme for synthesis of dopamine. Using phosphopeptide mapping, site-directed mutagenesis, and phosphorylation state-specific antibodies, the site was identified as Ser31, a previously defined extracellular signal-regulated kinases 1/2 (ERK1/2) site. The phosphorylation of Ser31 by Cdk5 versus ERK1/2 was investigated in intact mouse striatal tissue using a pharmacological approach. The results indicated that Cdk5 phosphorylates TH directly and also regulates ERK1/2-dependent phosphorylation of TH through the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1). Finally, phospho-Ser31 TH levels were increased in dopaminergic neurons of rats trained to chronically self-administer cocaine. These results demonstrate direct and indirect regulation of the phosphorylation state of a Cdk5/ERK1/2 site on TH and suggest a role for these pathways in the neuroadaptive changes associated with chronic cocaine exposure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02723.x
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  • 6
    Electronic Resource
    Electronic Resource
    Impairment of hippocampal long-term depression and defective spatial learning and memory in p35–/– mice (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 94 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35–/– mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35–/– mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35–/– mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which co-localized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03233.x
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  • 7
    Electronic Resource
    Electronic Resource
    Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 90 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Nicotine, acting on nicotinic acetylcholine receptors (nAChRs) expressed at pre-synaptic dopaminergic terminals, has been shown to stimulate the release of dopamine in the neostriatum. However, the molecular consequences of pre-synaptic nAChR activation in post-synaptic neostriatal neurons are not clearly understood. Here, we investigated the effect of nAChR activation on dopaminergic signaling in medium spiny neurons by measuring phosphorylated DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (the PKA-site) in mouse neostriatal slices. Nicotine produced dose-dependent responses, with a low concentration (1 µm) causing a sustained decrease in DARPP-32 Thr34 phosphorylation and a high concentration (100 µm) causing a transient increase in DARPP-32 Thr34 phosphorylation. Depending on the concentration of nicotine, either dopamine D2 or D1 receptor signaling was predominantly activated. Nicotine at a low concentration (1 µm) activated dopamine D2 receptor signaling in striatopallidal/indirect pathway neurons, likely by activating α4β2* nAChRs at dopaminergic terminals. Nicotine at a high concentration (100 µm) activated dopamine D1 receptor signaling in striatonigral/direct pathway neurons, likely by activating (i) α4β2* nAChRs at dopaminergic terminals and (ii) α7 nAChRs at glutamatergic terminals, which, by stimulating the release of glutamate, activated NMDA/AMPA receptors at dopaminergic terminals. The differential effects of low and high nicotine concentrations on D2- and D1-dependent signaling pathways in striatal neurons may contribute to dose-dependent actions of this drug of abuse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02574.x
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  • 8
    Electronic Resource
    Electronic Resource
    DARPP-32: An Integrator of Neurotransmission (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 269-296 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified initially as a major target for dopamine and protein kinase A (PKA) in striatum. However, recent advances now indicate that regulation of the state of DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34 and thereby converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5 and this converts DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. The state of phosphorylation of DARPP-32 at Thr34 depends on the phosphorylation state of two serine residues, Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. By virtue of its ability to modulate the activity of PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121415
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  • 9
    Electronic Resource
    Electronic Resource
    Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: involvement of glutamate signalling (2003)
    Oxford, UK : Blackwell Science, Ltd
    European journal of neuroscience 18 (2003), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neurotensin is a neuropeptide involved in dopaminergic signalling. We have recently reported that neurotensin stimulates the phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (PKA-site) by activating dopamine D1-type receptors in neostriatal neurons. DARPP-32 is also phosphorylated by cyclin-dependent kinase 5 on Thr75, and the phosphorylated form of DARPP-32 at Thr75 inhibits protein kinase (PKA) activity. In this study, we examined the effect of neurotensin on DARPP-32 Thr75 phosphorylation using mouse neostriatal slices. Neurotensin decreased the level of phospho-Thr75 DARPP-32 at 2 min of incubation, maximally to about 50% of control at a concentration of 1 µm. Pretreatment with a combined neurotensin receptor type 1 (NTR1)/type 2 (NTR2) antagonist, SR142948, reduced the basal level of phospho-Thr75 DARPP-32 and abolished the ability of neurotensin to decrease DARPP-32 Thr75 phosphorylation. However, neither an NTR1 antagonist, SR48692, an NTR2 antagonist, levocabastine, nor the two combined affected the basal level and the neurotensin-mediated decrease in DARPP-32 Thr75 phosphorylation. The effect of neurotensin was abolished by tetrodotoxin (TTX) or MK801 plus CNQX, but not by SCH23390 or raclopride. These results indicate that neurotensin stimulates the release of glutamate by activating a hypothesized unidentified neurotensin receptor, resulting in the dephosphorylation of DARPP-32 at Thr75 by activating NMDA and AMPA receptors expressed at medium spiny neurons. Thus, neurotensin, by removing the inhibition of PKA by phospho-Thr75 DARPP-32, potentiates its signalling via the dopamine/D1 receptor/PKA/phospho-Thr34 DARPP-32/PP-1 cascade.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1460-9568.2003.02859.x
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  • 10
    Electronic Resource
    Electronic Resource
    Requirement for DARPP-32 in mediating effect of dopamine D2 receptor activation (1999)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 11 (1999), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: It is well documented that dopamine and dopamine D1 agonists convert the protein phosphatase-1 inhibitor, DARPP-32, from its dephosphorylated, inactive form into its Thr34-phosphorylated, active form, and that these effects on DARPP-32 constitute essential components of the mechanism by which dopamine and D1 agonists achieve their biological effects. In contrast to dopamine and D1 agonists, dopamine D2 agonists dephosphorylate and inactivate DARPP-32. Here we have examined the possibility that the biological effects of dopamine D2 receptor agonists might also involve DARPP-32. For this purpose, we have examined regulation of the activity of the electrogenic ion pump Na+,K+-ATPase, an established target for dopamine signalling. We have found that dopamine D1 agonists and dopamine D2 agonists inhibit Na+,K+-ATPase activity in dissociated cells from the mouse neostriatum and that, in each case, the effect is abolished in cells from mice deficient in DARPP-32. We conclude that DARPP-32 may play an obligatory role in dopaminergic signalling mediated both by D1 receptors and by D2 receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1460-9568.1999.00724.x
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