Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex

Stanic, Jennifer; Carta, Mario; Eberini, Ivano; Pelucchi, Silvia; Marcello, Elena; Genazzani, Armando A.; Racca, Claudia; Mulle, Christophe; Luca, Mónica Di; Gardoni, Fabrizio

doi:10.1038/ncomms10181

Cited by 62 publications

(88 citation statements)

References 67 publications

(102 reference statements)

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“…Lyophilized CPPs were resuspended in sterile deionized water and used at the final concentration of 10 μM for pull-down treatments, 20 μM for hippocampal culture treatments whereas were administered by intraperitoneal injection at 3 nmol g −1 in vivo 66.…”

Section: Methodsmentioning

confidence: 99%

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

et al. 2017

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Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABAB receptors (GABABRs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABABR activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABABRs and extrasynaptic δ-subunit-containing GABAARs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABABR-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy.

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Section: Methodsmentioning

confidence: 99%

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

et al. 2017

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“…Additionally, rabphilin‐3A controls repriming of vesicles after extensive synaptic activity . Their location is not limited to the presynaptic compartment, as they are also present in the postsynaptic compartment, in which rabphilin‐3A interacts with GluN2A and postsynaptic density protein 95, forming a complex that regulates N ‐methyl‐ d ‐aspartate receptor stabilization . We also reported its expression in the neurohypophysis and in AVP neurons in the SON .…”

Section: Discussionmentioning

confidence: 76%

Critical role of rabphilin‐3A in the pathophysiology of experimental lymphocytic neurohypophysitis

Yasuda

Iwama

Kiyota

et al. 2018

The Journal of Pathology

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Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3 T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3 T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…interactions (Stanic et al, 2015), the membrane trafficking SYT12, the neuropeptide VGF and the adenylyl cyclase pathway molecules ADCY1 and PDE4A, and KCN channel components. (Wilson, Bienias, Evans, & Bennett, 2004;Wilson et al, 2002…”

Section: Gene Set Enrichment Analysis Of Cognitively Contrasted Samplesmentioning

confidence: 99%

Multiplexed fractionated proteomics reveals synaptic factors associated with cognitive resilience in Alzheimer's Disease

Carlyle

Kandigian

Kreuzer

et al. 2020

Preprint

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Alzheimer's disease (AD) is a complex neurodegenerative disease defined by the presence of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, and driven by dysproteostatis, inflammation, metabolic dysfunction, and oxidative injury, eventually leading to synapse loss and cell death. Synapse loss correlates with cognitive impairment and may occur independently of the extent of AD pathology. To understand how synaptic composition is changed in relation to AD neuropathology and cognition, highly sensitive multiplexed liquid chromatography mass-spectrometry was used to quantify biochemically enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting AD pathology and cognitive performance. Functional analysis showed preservation of synaptic signaling, ion transport, and mitochondrial proteins in normal aged and "resilient" (cognitively unimpaired with AD pathology) individuals. Compared to these individuals, those with cognitive impairment showed significant metabolic differences and increased immune- and inflammatory-related proteins, establishing the synapse as a potential integration point for multiple AD pathophysiologies.

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Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex

Cited by 62 publications

References 67 publications

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

Critical role of rabphilin‐3A in the pathophysiology of experimental lymphocytic neurohypophysitis

Multiplexed fractionated proteomics reveals synaptic factors associated with cognitive resilience in Alzheimer's Disease

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