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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    Electronic Resource
    Electronic Resource
    Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Glutamatergic inputs from corticostriatal and thalamostriatal pathways have been shown to modulate dopaminergic signaling in neostriatal neurons. DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) is a signal transduction molecule that regulates the efficacy of dopamine signaling in neostriatal neurons. Dopamine signaling is mediated in part through phosphorylation of DARPP-32 at Thr34 by cAMP-dependent protein kinase, and antagonized by phosphorylation of DARPP-32 at Thr75 by cyclin-dependent protein kinase 5. We have now investigated the effects of the ionotropic glutamate NMDA and AMPA receptors on DARPP-32 phosphorylation in neostriatal slices. Activation of NMDA and AMPA receptors decreased the state of phosphorylation of DARPP-32 at Thr34 and Thr75. The decrease in Thr34 phosphorylation was mediated through Ca2+-dependent activation of the Ca2+-/calmodulin-dependent phosphatase, calcineurin. In contrast, the decrease in Thr75 phosphorylation was mediated through Ca2+-dependent activation of dephosphorylation by protein phosphatase-2A. The results provide support for a complex effect of glutamate on dopaminergic signaling through the regulation of dephosphorylation of different sites of DARPP-32 by different protein phosphatases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00876.x
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  • 6
    Electronic Resource
    Electronic Resource
    Neurotensin regulates DARPP-32 Thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cAMP-dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP 1). Here, we examined the effect of neurotensin on DARPP-32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP-32 Thr34 phosphorylation by 4–7-fold with a K0.5 of ∼50 nm. The effect of neurotensin was antagonized by a combined neurotensin receptor type-1 (NTR1)/type-2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor- and AMPA receptor-dependent manner, leading to the increase in DARPP-32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild-type mice but not in DARPP-32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1-receptor/cAMP/PKA/DARPP-32/PP 1 cascade.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00822.x
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