Internalization of ionotropic glutamate receptors in response to mGluR activation

Snyder, Eric M.; Philpot, Benjamin D.; Huber, Kimberly M.; Dong, Xin; Fallon, Justin R.; Bear, Mark F.

doi:10.1038/nn746

Cited by 498 publications

(537 citation statements)

References 33 publications

Supporting

Mentioning

490

Contrasting

Unclassified

Order By: Relevance

“…The G q -coupled mGlu5 is highly expressed at excitatory synapses in the CA1 hippocampal neurons (Lujan et al, 1996) and contributes to a number of postsynaptic functions in the central nervous system, such as increased neuronal excitability, intracellular Ca 21 increase, synaptic plasticity, and pain (Snyder et al, 2001;Ireland and Abraham, 2002;Gubellini et al, 2003;Rae and Irving, 2004). Homer proteins are known to link mGluRs to other postsynaptic density proteins (Shiraishi-Yamaguchi and Furuichi, 2007;Niswender and Conn, 2010) and play a vital role in coupling the receptors with downstream effectors (Mao et al, 2005;Jung et al, 2007;Won et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of mGlu5 leads to a protein-translation-dependent increase in mediators involved in AMPA receptor endocytosis (Snyder et al, 2001;Bear et al, 2004). Since mGlu5-mediated protein synthesis was abolished by GluD1 deletion, we investigated whether mGlu5-mediated AMPA receptor internalization was also affected in GluD1 KO.…”

Section: Glud1 Regulates Mglu5 Signalingmentioning

confidence: 99%

See 1 more Smart Citation

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

et al. 2016

View full text Add to dashboard Cite

The delta family of ionotropic glutamate receptors consists of glutamate delta-1 (GluD1) and glutamate delta-2 receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in the N-methyl-D-aspartate receptor subunit, which are relevant to autism and other neurodevelopmental disorders. Here, we identified a novel role of GluD1 in regulating metabotropic glutamate receptor 5 (mGlu5) signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1 protein coimmunoprecipitated with mGlu5 in the hippocampal membrane fraction, as well as when overexpressed in human embryonic kidney 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold protein effector Homer, which regulates mechanistic target of rapamycin (mTOR) signaling, was abnormal both under basal conditions and in response to mGlu1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in GluD1 knockout mice. The basal levels of phosphorylated mTOR and protein kinase B, the signaling proteins downstream of mGlu5 activation, were higher in GluD1 knockout mice, and no further increase was induced by DHPG. We also observed higher basal protein translation and an absence of DHPG-induced increase in GluD1 knockout mice. In accordance with a role of mGlu5-mediated mTOR signaling in synaptic plasticity, DHPG-induced internalization of surface a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interacts with mGlu5, and loss of GluD1 impairs normal mGlu5 signaling potentially by dysregulating coupling to its effector. These studies identify a novel role of the enigmatic GluD1 subunit in hippocampal function.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Glud1 Regulates Mglu5 Signalingmentioning

confidence: 99%

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Although this seems to be the case in mature neurons, NMDARs move rapidly into and out of synapses in developing neurons 15,18,34 . It is likely that synaptic removal of NMDARs involves a combination of lateral diffusion 15,34 and endocytosis [16][17][18] . Although the mechanisms have been unclear, this process is almost certainly determined by a balance between interactions with scaffolding proteins that anchor receptors at the PSD, and interactions with adaptors that target NMDARs to the endocytic machinery for membrane removal 25 .…”

Section: Nmdar Mobility and Receptor Endocytosismentioning

confidence: 99%

“…Substantial evidence also supports a role for exocytic and endocytic receptor cycling in controlling AMPAtype glutamate receptor abundance at synapses during synaptic plasticity, but NMDARs have conventionally been thought to be stably fixed within the postsynaptic density (PSD). Challenging this view, recent studies have revealed that NMDARs can move rapidly in and out of the neuronal surface [14][15][16][17][18][19][20] . Atleast some forms of NMDAR exocytic and endocytic trafficking require synaptic activity 21 or ligand binding 17,22 ,23 , and may initiate synaptic changes that lead to synapse stabilization or elimination during development 16,23 . Despite recent progress, our knowledge of how postsynaptic NMDARs are linked to and regulated by the endocytic machinery is only just emerging.…”

mentioning

confidence: 99%

Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1

et al. 2006

View full text Add to dashboard Cite

A key step in glutamatergic synapse maturation is the replacement of developmentally expressed N-methyl-D-aspartate receptors (NMDARs) with mature forms that differ in subunit composition, electrophysiological properties and propensity to elicit synaptic plasticity. However, the mechanisms underlying the removal and replacement of synaptic NMDARs are poorly understood. Here we demonstrate that NMDARs containing the developmentally regulated NR3A subunit undergo rapid endocytosis from the dendritic plasma membrane in cultured rat hippocampal neurons. This endocytic removal is regulated by PACSIN1/syndapin1, which directly and selectively binds the carboxy-terminal domain of NR3A through its NPF motifs and assembles a complex of proteins including dynamin and clathrin. Endocytosis of NR3A by PACSIN1 is activity dependent, and disruption of PACSIN1 function causes NR3A accumulation at synaptic sites. Our results reveal a new activity-dependent mechanism involved in the regulation of NMDAR expression at synapses during development, and identify a brain-specific endocytic adaptor that confers spatiotemporal and subunit specificity to NMDAR endocytosis.Stabilization and maturation of synapses is central to neural circuit formation. During development, excitatory synapses in the central nervous system are remodeled in response to

show abstract

“…The involvement of the mGluRs in hippocampal LTD has been well established (Bolshakov and Siegelbaum, 1994;Fitzjohn et al, 1999;O'Mara et al, 1995;Snyder et al, 2001), however their contribution to LTP has been a subject of unresolved debate (Bashir et al, 1993;Bortolotto et al, 1995;Chinestra et al, 1993;Manzoni et al, 1994;Richter-Levin et al, 1994;Riedel et al, 1995;Selig et al, 1995). To date, eight mGluR subtypes, designated mGluR1 to mGluR8, have been cloned from the mammalian brain.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Cumiskey¹,

Butler²,

Moynagh³

et al. 2007

Brain Research

View full text Add to dashboard Cite

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-α, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-α on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-α is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-α is now known to cause transient increases in intracellular Ca 2+ levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca 2+ homeostasis could be involved.Ryanodine was found to significantly reverse the inhibition of LTP by TNF-α. From these studies we propose that the TNF-α inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca 2+ stores in TNF-α mediated inhibition of LTP. IntroductionThe pro-inflammatory cytokine tumor-necrosis factor (TNF)-α is elevated in the brain in a number of neuropathological states including trauma, ischemia, Parkinson's disease, multiple sclerosis and HIV-associated dementia (Iida et al., 2000;Kassiotis and Kollias, 2001;Sriram et al., 2002). The signaling mechanism underlying the ability of TNF-α to cause the cognitive dysfunction associated with many of these conditions has been probed, but to date no clear mechanistic understanding has been reached. TNF-α and IL-1β at pathophysiological levels have been shown by many authors to inhibit long-term potentiation (LTP) in the CA1 and the dentate gyrus regions of the rat hippocampus (Cunningham et al., 1996;Murray and Lynch, 1998;Tancredi et al., 1992) but not by others (Stellwagen and Malenka, 2006). IL-1β has been shown to depress NMDAreceptor mediated field potentials in the dentate gyrus (Coogan B R A I N R E S E A R C H 1 1 3 6 ( 2 0 0 7 ) 1 3 -1 9 ⁎ Corresponding author.

show abstract

Internalization of ionotropic glutamate receptors in response to mGluR activation

Cited by 498 publications

References 33 publications

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Contact Info

Product

Resources

About