Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo

Nagai, Taku; Nakamuta, Shinichi; Kuroda, Kensuke; Nakauchi, Sakura; Nishioka, Tomoki; Takano, Tetsuya; Zhang, Xinjian; Tsuboi, Daisuke; Funahashi, Yasuhiro; Nakano, T.; Yoshimoto, Junichiro; Kobayashi, Kenta; Uchigashima, Motokazu; Watanabe, Masahiko; Miura, Masami; Nishi, Akinori; Kobayashi, Kazuto; Yamada, Kiyofumi; Amano, Mutsuki; Kaibuchi, Kozo

doi:10.1016/j.neuron.2015.12.019

Cited by 89 publications

(124 citation statements)

References 76 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…In addition to ERK1/2, PKA has also been shown to phosphorylate RasGRP2 at multiple sites [26,27,28]. However, these studies have produced conflicting results.…”

Section: Discussionmentioning

confidence: 99%

“…However, these studies have produced conflicting results. In the original studies [26,27], phosphorylation by PKA resulted in the inhibition of RasGRP2 in HEK293T cells, while the most recent study showed PKA-mediated activation of RasGRP2 in Cos-7 cells [28]. It is difficult to reconcile these results and perhaps future studies using purified proteins will clarify this issue.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

Ren

Cook

Bergmeier

et al. 2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The dynamic regulation of ERK1 and −2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf–MEK–ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2.

show abstract

“…In addition to ERK1/2, PKA has also been shown to phosphorylate RasGRP2 at multiple sites [26,27,28]. However, these studies have produced conflicting results.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

Ren

Cook

Bergmeier

et al. 2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…Using tissue punches taken from the PAG, we detected a rapid and significant increase in pERK1,2, but not pCREB, in response to systemic administration of a D1/5 receptor agonist. Examples of previous studies relevant to our study have shown that (1) activation of D1 receptors by SKF 81297 can increase pERK (Gangarossa et al, 2012; Gangarossa et al, 2013, (2) that the increase in pERK by SKF 81297 can be blocked by the D1 receptor antagonist SCH23390 (Gangarossa et al, 2011), and (3) that the SKF 81297-mediated increase in pERK is PKA-dependent (Florentini et al, 2011; Nagai et al, 2016). To be clear, ERK1,2 is believed to be activated indirectly by PKA through other mechanisms, including Ras/Raf/Rap or the cAMP-dependent, PKA-independent exchange protein Epac (Kawasaki et al, 1998; Gelinas et al, 2008).…”

Section: Dopamine Receptor Function/signal Transduction In the Pagmentioning

confidence: 62%

Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

Voulalas

Jiang

et al. 2017

Neuroscience

View full text Add to dashboard Cite

Neuropathic pain resulting from spinal cord injury is often accompanied by maladaptive plasticity of the central nervous system, including the opioid receptor-rich periaqueductal gray (PAG). Evidence suggests that sensory signaling via the PAG is robustly modulated by dopamine D1- and D2-like receptors, but the effect of damage to the spinal cord on D1 and D2 receptor protein expression and function in the PAG has not been examined. Here we show that 21 days after a T10 or C6 spinothalamic tract lesion, both mice and rats display a remarkable decline in the expression of D1 receptors in the PAG, revealed by western blot analysis. These changes were associated with a significant reduction in hindpaw withdrawal thresholds in lesioned animals compared to sham-operated controls. We investigated the consequences of diminished D1 receptor levels by quantifying D1-like receptor-mediated phosphorylation of ERK1,2 and CREB, events that have been observed in numerous brain structures. In naïve animals, western blot analysis revealed that ERK1,2, but not CREB phosphorylation was significantly increased in the PAG by the D1-like agonist SKF 81297. Using immunohistochemistry, we found that SKF 81297 increased ERK1,2 phosphorylation in the PAG of sham animals. However, in lesioned animals, basal pERK1,2 levels were elevated and did not significantly increase after exposure to SKF 81297. Our findings provide support for the hypothesis that molecular adaptions resulting in a decrease in D1 receptor expression and signaling in the PAG are a consequence of SCL.

show abstract

“…In order to construct pAAV‐syn‐tTA‐nls, tTA‐nls was subcloned into the BamHI and Hind III sites of pAAV‐syn‐GFP. AAV was prepared as described previously . AAV titers were estimated via a quantitative polymerase chain reaction.…”

Section: Methodsmentioning

confidence: 99%

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice

Wulaer

Nagai

Sobue

et al. 2018

Genes Brain and Behavior

View full text Add to dashboard Cite

Disrupted-in-schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1 mice), which have a deficiency of the full-length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen-based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild-type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c-Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine-N-oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1 mice are associated with hyperactivity of the DMS.

show abstract

Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo

Cited by 89 publications

References 76 publications

A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice

Contact Info

Product

Resources

About

Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo

Cited by 89 publications

References 76 publications

A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1Δ2‐3/Δ2‐3 mice

Contact Info

Product

Resources

About

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice