Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution

Nishi, Akinori; Matamales, Miriam; Musante, Veronica; Valjent, Emmanuel; Kuroiwa, Mahomi; Kitahara, Yosuke; Rebholz, Heike; Greengard, Paul; Girault, Jean‐Antoine; Nairn, Angus C.

doi:10.1074/jbc.m116.752402

Cited by 23 publications

(24 citation statements)

References 41 publications

(91 reference statements)

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“…As it is known, there are multiple other neurotransmitters besides dopamine that regulate the excitability of dopaminoceptive neurons: glutamate, GABA, opiates, and adenosine, which are involved in signaling through DARPP-32 in MSNs [28]. In particular, in our previous studies the expression rates of catecholaminergic, glutamatergic and GABAergic receptors in the dorsal striatum were shown to be significantly altered as compared to the control group, in reverse directions for the defeated and aggressive mice [25,26].…”

Section: Glutamate Vs Dopamine Gradient In Msn Statesmentioning

confidence: 92%

“…To gain fuller insight into the D1/D2 MSNs we retrieved the annotated genes implicated in PP1-regulated phosphorylation pathways in MSNs based on available literature [14,23,[27][28][29]. The compiled core gene set comprising cAMP-mediated dopamine response genes, expanded with NMDA glutamate receptor subunits Grina, Grin1-Grin2 and MAP kinases is presented in Table 1.…”

Section: Compilation Of Gene Setsmentioning

confidence: 99%

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Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

et al. 2020

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Background: Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)-mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. Results: A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1-and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. Conclusion: Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.

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Section: Glutamate Vs Dopamine Gradient In Msn Statesmentioning

confidence: 92%

Section: Compilation Of Gene Setsmentioning

confidence: 99%

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

et al. 2020

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“…In vitro experiments on striatal neurons have recently revealed that dephosphorylation at the Thr34, Thr75, and Ser97 residues by PP2A/PR72 leads to nuclear accumulation of an inactive form of DARPP‐32 (Nishi et al . ). Thus, glutamate transmission may counteract dopamine D1 receptor signaling also through this mechanism.…”

Section: Dopamine and Darpp‐32 Signaling Pathwaysmentioning

confidence: 97%

“…Under basal conditions, DARPP‐32 is mainly phosphorylated at Thr75, Ser97, and Ser130 residues (Nishi et al . ) and acts as a PKA inhibitor (Fig. a).…”

Section: Dopamine and Darpp‐32 Signaling Pathwaysmentioning

confidence: 99%

DARPP‐32 in the orchestration of responses to positive natural stimuli

Scheggi

Montis

Gambarana

2018

Journal of Neurochemistry

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Dopamine- and cAMP-regulated phosphoprotein (M 32 kDa, DARPP-32) is an integrator of multiple neuronal signals and plays a crucial role particularly in mediating the dopaminergic component of the systems involved in the evaluation of stimuli and the ensuing elaboration of complex behavioral responses (e.g., responses to reinforcers and stressors). Dopamine neurons can fire tonically or phasically in distinct timescales and in specific brain regions to code different behaviorally relevant information. Dopamine signaling is mediated mainly through the regulation of adenylyl cyclase activity, stimulated by D1-like or inhibited by D2-like receptors, respectively, that modulates cAMP-dependent protein kinase (PKA) function. The activity of DARPP-32 is finely regulated by its phosphorylation at multiple sites. Phosphorylation at the threonine (Thr) 34 residue by PKA converts DARPP-32 into an inhibitor of protein phosphatase 1, while the phosphorylation at the Thr75 residue turns it into an inhibitor of PKA. Thus, DARPP-32 is critically implicated in regulating striatal output in response to the convergent pathways that influence signaling of the cAMP/PKA pathway. This review summarizes some of the landmark and recent studies of DARPP-32-mediated signaling in the attempt to clarify the role played by DARPP-32 in the response to rewarding natural stimuli. Particularly, the review deals with data derived from rodents studies and discusses the involvement of the cAMP/PKA/DARPP-32 pathway in: 1) appetitive food-sustained motivated behaviors, 2) motivated behaviors sustained by social reward, 3) sexual behavior, and 4) responses to environmental enrichment.

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“…The activation of dopaminergic and glutamatergic receptors regulates the phosphorylation of DARPP-32, but with opposite molecular mechanisms. Thus, the stimulation of dopamine D 1 receptor enhances the phosphorylation by PKA of Thr-34 site in DARPP-32 [Walaas et al, 1983;Walaas and Greengard, 1984], which acts as a strong PP1 inhibitor , whereas the activation of the NMDA receptor promotes the elevation of intracellular calcium, inducing dephosphorylation of DARPP-32 [Halpain et al, 1990;Nishi et al, 2005Nishi et al, , 2017 and reducing its PP1 inhibitory activity. In addition, DARPP-32 is phosphorylated/dephosphorylated by several other kinases and phosphatases with multiple cellular responses, including the regulation of cytonuclear trafficking and chromatin response [Johansen and Johansen, 2006;Stipanovich et al, 2008;Yger and Girault, 2011].…”

mentioning

confidence: 99%

Immunohistochemical Localization of DARPP-32 in the Brain of Two Lungfishes: Further Assessment of Its Relationship with the Dopaminergic System

López

Morona²,

González³

2017

Brain Behav Evol

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The distribution of DARPP-32 (a phosphoprotein related to the dopamine D₁ receptor) has been widely used as a means to clarify the brain regions with dopaminoceptive cells, primarily in representative species of tetrapods. The relationship between dopaminergic and dopaminoceptive elements is frequently analyzed using the catecholamine marker tyrosine hydroxylase (TH). In the present study, by means of combined immunohistochemistry, we have analyzed these relationships in lungfishes, the only group of sarcopterygian fishes represented by 6 extant species that are the phylogenetically closest living relatives of tetrapods. We used the Australian lungfish Neoceratodus forsteri and the African lungfish Protopterus dolloi. The DARPP-32 antibody yields a distinct and consistent pattern of neuronal staining in brain areas that, in general, coincide with areas that are densely innervated by TH-immunoreactive fibers. The striatum, thalamus, optic tectum, and torus semicircularis contain intensely DARPP-32-immunoreactive cell bodies and fibers. Cells are also located in the olfactory bulbs, amygdaloid complex, lateral septum, pallidum, preoptic area, suprachiasmatic nucleus, tuberal hypothalamic region, rostral rhombencephalic reticular formation, superior raphe nucleus, octavolateral area, solitary tract nucleus, and spinal cord. Remarkably, DARPP-32-immunoreactive fibers originating in the striatum reach the region of the dopaminergic cells in the mesencephalic tegmentum and represent a well-established striatonigral pathway in lungfishes. Double immunolabeling reveals that DARPP-32 is present in neurons that most likely receive TH input, but it is absent from the catecholaminergic neurons themselves, with the only exception of a few cells in the suprachiasmatic nucleus of Neoceratodus and the solitary tract nucleus of Protopterus. In addition, some species differences exist in the localization of DARPP-32 cells in the pallium, lateral amygdala, thalamus, prethalamus, and octavolateral area. In general, the present study demonstrates that the distribution pattern of DARPP-32, and its relationship with TH, is largely comparable to those reported for tetrapods, highlighting a shared situation among all sarcopterygians.

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Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution

Cited by 23 publications

References 41 publications

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

DARPP‐32 in the orchestration of responses to positive natural stimuli

Immunohistochemical Localization of DARPP-32 in the Brain of Two Lungfishes: Further Assessment of Its Relationship with the Dopaminergic System

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