NCS-Rapgef2, the Protein Product of the Neuronal<i>Rapgef2</i>Gene, Is a Specific Activator of D1 Dopamine Receptor-Dependent ERK Phosphorylation in Mouse Brain

Jiang, Sunny Zhihong; Xu, W.; Emery, Andrew C.; Gerfen, Charles R.; Eiden, Maribeth V.; Eiden, Lee E.

doi:10.1523/eneuro.0248-17.2017

Cited by 27 publications

(69 citation statements)

References 71 publications

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“…The triggering events in D1Rdependent ERK activation, meanwhile, involve synergistic intracellular events. In fact, cAMP-mediated mechanisms involving the PKA-dependent recruitment of Rasgrp2 and/or the activation of the cAMP sensor NCS-Rapgef2 have been recently unveiled (Nagai et al 2016;Jiang et al 2017). Moreover, ERK activation in D1R-SPNs has also been shown to rely on the activation of Fyn which, by phosphorylating GluN2B of NMDAR, leads to an increase of calcium influx and a subsequent activation of the Ras-GRF1/ERK cascade (Fasano et al 2009;Pascoli et al 2011;Jin et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

Gangarossa

Castell

Castro³

et al. 2019

Preprint

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All custom-made materials will be shared upon reasonable request. Running title: ERK, dopamine and the caudal striatumKeywords: striatum, dopamine, ERK, D1R, D2R, psychostimulants ERK, dopamine and the caudal striatum 2 AbstractThe caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of paramount importance to understand its functions, which remain largely elusive.Taking advantage of genetically encoded biosensors (A-kinase activity reporter 3, AKAR3) to record PKA signals and by analyzing the distribution of dopamine D1Rand D2R-SPNs in the TS, we characterized three subterritories: a D2R/A2aR-lacking, a D1R/D2R-intermingled and a D1R/D2R-SPNs-enriched area (corresponding to the amygdalostriatal transition). In addition, we provide evidence that the distribution of D1R-and D2R-SPNs in the TS is evolutionarily conserved (mouse, rat, gerbil). The in vivo analysis of extracellular signal-regulated kinase (ERK) phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate aversive responses, fasting, satiety or palatable signals whereas a reduction in ERK phosphorylation occurred following learned avoidance. In contrast, D1R-SPNs of the intermingled and D2R/A2aR-lacking areas were strongly activated by both D1R agonists and psychostimulant drugs (d-amphetamine, cocaine, MDMA or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals and discrete aversive stimuli.ERK, dopamine and the caudal striatum 3

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Section: Discussionmentioning

confidence: 99%

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

Gangarossa

Castell

Castro³

et al. 2019

Preprint

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“…Animal care, drug treatment and surgeries were approved by the NIMH Institutional Animal Care and Use Committee (ACUC) and conducted in accordance with the NIH guidelines. The floxed Rapgef2 mouse strain Rapgef2 cko/cko and corticolimbic Rapgef2 KO mouse strain Camk2α-cre +/-::Rapgef2 cko/cko were generated as described previously (Jiang et al, 2017). The transgenic Drd1a-tdTomato BAC mouse (The Jackson Laboratory, #016204), expressing tdTomato selectively in D1-dopaminoceptive neurons (Shuen et al, 2008), was obtained from the Jackson Laboratory.…”

Section: Animals and Drugs Administered In Vivomentioning

confidence: 99%

“…NS-1 cells (Emery et al, 2013) were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 10% HyClone horse serum (GE Healthcare, Marlborough, MA), 5% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin. The established NS-1 cell line with NCS-Rapgef2 knocked-out was described previously (Jiang et al, 2017). The cell-permeable cyclic AMP analog 8-chlorophenylthio-cyclic AMP (8-CPT-cAMP) was purchased from Biolog Life Science Institute (Bremen, Germany) and the stock solution was prepared at 100 mM in DMSO, diluted in culture media to a final concentration of 100 μM.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…Immunohistochemistry was conducted as previously described (Jiang et al, 2017) after animal perfusion with 4% paraformaldehyde. Mouse brains were sectioned by Vibratome at a 40 μm thickness.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…We have previously identified a novel pathway for ERK activation via the novel cAMP effector NCS-Rapgef2 in NS-1 neuroendocrine cells in culture (Emery and Eiden, 2012;Emery et al, 2013;Emery et al, 2014;Emery et al, 2017a). NCS-Rapgef2 is activated by cAMP binding to facilitate GDP-GTP exchange on the Rap1 molecule, allowing Rap1 to further stimulate the MAP kinase cascade culminating in ERK phosphorylation/activation (see Jiang et al, 2017). Using this assay as a read-out for the NCS-Rapgef2 dependent cAMP pathway, we have shown that the dopamine D1 receptor couples to NCS-Rapgef2 to activate ERK in neuroendocrine cells, and further demonstrated that this pathway is required for D1-dependent activation of ERK in hippocampus and other forebrain regions of the adult mouse brain in vivo (Jiang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Cocaine-dependent acquisition of locomotor sensitization and conditioned place preference requires D1 dopaminergic signaling through a cyclic AMP, NCS-Rapgef2, ERK and Egr-1/Zif268 pathway

Jiang

Sweat

Dahlke

et al. 2020

Preprint

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ABSTRACTElucidation of the underlying mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor expressingneurons leadingto acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK→Egr-1/zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons (MSNs) of nucleus accumbens slices; and in mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the nucleus accumbens (NAc) in adult mice, using AAV-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-MSNs and cocaine-induced behaviors including locomotor sensitization and conditioned place preference (CPP). Abrogation of NCS-Rapgef2 gene expression in medium prefrontal cortex and basolateral amygdala, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase IIα promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1-receptor expressing neurons in the NAc, butnotin corticolimbic areas, contributes to cocaine-induced locomotor sensitization and CPP. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling.SIGNIFICANCE STATEMENTERK phosphorylation in dopamine D1 receptor expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioraladaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the nucleus accumbens is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequentenhanced locomotor response anddrugseeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-MSNs encode the experience of psychomotor stimulant exposure.

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The guanine nucleotide exchange factor RapGEF2 is required for ERK-dependent immediate-early gene (Egr1) activation during fear memory formation

Jiang,

Shahoha,

Zhang

et al. 2024

Cell. Mol. Life Sci.

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NCS-Rapgef2, the Protein Product of the NeuronalRapgef2Gene, Is a Specific Activator of D1 Dopamine Receptor-Dependent ERK Phosphorylation in Mouse Brain

Abstract: Visual Abstract

Cited by 27 publications

References 71 publications

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

Cocaine-dependent acquisition of locomotor sensitization and conditioned place preference requires D1 dopaminergic signaling through a cyclic AMP, NCS-Rapgef2, ERK and Egr-1/Zif268 pathway

The guanine nucleotide exchange factor RapGEF2 is required for ERK-dependent immediate-early gene (Egr1) activation during fear memory formation

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