Rap2-JNK Removes Synaptic AMPA Receptors during Depotentiation

Zhu, Yingting; Pak, Daniel T.S.; Qin, Yi; McCormack, Stefanie G.; Kim, Myung J.; Baumgart, Joel P.; Velamoor, Vanisree; Auberson, Yves P.; Osten, Pavel; Aelst, Linda Van; Sheng, Morgan; Zhu, Jie

doi:10.1016/j.neuron.2005.06.022

Cited by 48 publications

(126 citation statements)

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“…Our present data suggest dysregulated localization and function of NMDA receptors. For example, increased phosphorylation of Y1336 NR2B, which targets NMDARs to extrasynaptic sites, suggests abnormal localization of NMDARs in the DLPFC (Figure 2) (Goebel-Goody et al, 2009;Zhu et al, 2005). This is consistent with the finding of decreased phospho-NR1, suggesting decreased NMDA receptors or altered subunit stoichiometry at synaptic sites (Emamian et al, 2004).…”

Section: Discussionsupporting

confidence: 82%

“…Thus, our data suggest less synapticallylocalized PSD-95, which may induce AMPAR internalization and induction of LTD in the ACC (Kim et al, 2007). Additionally, Rap2, a member of the Ras family of GTPases, indirectly activates JNK (Figure 3), and Rap2-JNK interactions traffic AMPA receptors away from the synapse during LTD, or bidirectionally in an activity dependent manner (Hussain et al, 2010;Thomas et al, 2008;Zhu et al, 2005). Interestingly, Rap2 function is modulated by SynGAP, a Ras and Rap GTPase-activating-protein, by its C2 domain (Funk et al, 2009;Pena et al, 2008).…”

Section: Discussionmentioning

confidence: 74%

“…Extrasynaptic NR2B-containing NMDARs regulate NR2A function, potentially altering synapse development and plasticity (Kollen et al, 2008;Zhu et al, 2005). Consistent with abnormal synaptic NMDAR composition and the potential impact on plasticity, subunit specific transcript studies show decreased NR2D expression in multiple regions in schizophrenia (Harney et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

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Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

133

102

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Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3 0 -5 0 -cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK-and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC ¼ 36, DLPFC ¼ 35) and a comparison (ACC ¼ 33, DLPFC ¼ 31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK-and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK-and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK-and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 98%

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Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

133

102

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“…1D) and may be enriched in Triton-X 100 insoluble postsynaptic densities (18), i.e., well-established focal points for synaptic plasticityrelated signaling. RGS14 binding partners H-Ras and Rap2 modulate the activity of various MAP kinase pathways in hippocampal neurons (34) and have been implicated in different aspects of LTP and synaptic plasticity in the hippocampus (34)(35)(36)(37)(38)(39)(40)(41). However, RGS14 also binds Gi/o family members at both the GPR domain and the RGS domain, and our findings do not rule out a possible role for RGS14 regulation of Gi/o protein signaling in this process.…”

Section: Discussionmentioning

confidence: 54%

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

Lee¹,

Simons

Heldt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

181

349

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Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG-CA3-CA1 circuit.long-term potentiation | hippocampus | G protein signaling | RGS proteins | ERK

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“…Thus, JNK contributes to bone morphogenic proteinstimulated dendrite formation (Podkowa et al 2010), the structure of dendritic architecture (Coffey et al 2000;Bjorkblom et al 2005), axodendritic length (Tararuk et al 2006), and axonal regeneration (Barnat et al 2010). Moreover, JNK can regulate kinesin-mediated fast axonal transport on microtubules (Morfini et al 2006(Morfini et al , 2009) and contributes to the regulation of synaptic plasticity (Chen et al 2005;Zhu et al 2005;Li et al 2007; Thomas et al 2008). Together, these data demonstrate that JNK plays a key role in the physiological regulation of neuronal activity (Waetzig et al 2006).…”

mentioning

confidence: 94%

JNK regulates FoxO-dependent autophagy in neurons

Xu¹,

Das²,

Reilly³

et al. 2011

Genes Dev.

199

176

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The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.

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Rap2-JNK Removes Synaptic AMPA Receptors during Depotentiation

Cited by 48 publications

References 0 publications

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

JNK regulates FoxO-dependent autophagy in neurons

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