A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux

Vissel, Bryce; Krupp, Johannes; Heinemann, Stephen F.; Westbrook, Gary L.

doi:10.1038/88404

Cited by 230 publications

(233 citation statements)

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“…Several mechanisms have been proposed for the regulation of NMDAR functions, including altering the phosphorylation state and biophysical properties of the channel (47,48) and changing NMDAR trafficking and channel numbers at the membrane (49,50). Our previous finding suggests that 5-HT 1A decreases surface NR2B clusters in a microtubule-dependent manner (21), consistent with the role of cytoskeleton-based transport on NMDAR insertion to the plasma membrane (51,52).…”

Section: Discussionsupporting

confidence: 64%

Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Yuen

Jiang

Chen

et al. 2008

Journal of Biological Chemistry

113

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Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT 1A Serotonin (5-HT)2 is a key neuromodulator mediating diverse cognitive and emotional functions in the central nervous system (1). The pleiotropic functions of serotonin are afforded by the concerted actions of multiple 5-HT receptor subtypes, 5-HT 1 -to 5-HT 7 (2, 3). Mice lacking 5-HT receptors exhibit phenotypes ranging from increased anxiety (4), to elevated aggression (5), to antidepressant-like behaviors (6). One of the major targets of serotonin is prefrontal cortex (PFC), a crucial brain region controlling emotion and cognition (7,8). Several lines of evidence have shown that 5-HT 1A and 5-HT 2A receptors, which are abundantly co-expressed in most of PFC pyramidal neurons (9), often have opposing actions on common substrates. For instance, activation of 5-HT 1A receptors results in neuronal inhibition by increasing potassium currents (10) and decreasing calcium currents (11). In contrast, 5-HT 2A receptor stimulation leads to neuronal excitation by suppressing potassium currents (2) and enhancing pre-synaptic glutamate release (12). Moreover, elevated 5-HT 1A receptors and reduced 5-HT 2A receptors are found in PFC of schizophrenia patients (13,14), suggesting that the levels of 5-HT 1A and 5-HT 2A receptors are differentially altered in diseased states.One of the potential cellular targets of 5-HT receptors involved in cognitive and emotional control is the NMDA-type glutamate receptor, a ligand-gated ion channel that has been implicated in the pathophysiology of mental disorders (15). NMDAR hypofunction caused by systemic administration of non-competitive NMDAR antagonists or knockdown of NMDAR expression produces schizophrenia-like behavioral symptoms (16 -18). Moreover, it has been found that the expression of NMDARs is reduced in postmortem brains of depressed patients (19), and chronic antidepressant treatment enhances NMDAR levels in mouse brains (20). Our previous study has shown that activation of 5-HT 1A receptors suppresses NMDAR channel function in PFC pyramidal neurons (21). It remains unknown whether 5-HT 2A receptor activation has any impact on the 5-HT 1A -NMDAR interaction.

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Section: Discussionsupporting

confidence: 64%

Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Yuen

Jiang

Chen

et al. 2008

Journal of Biological Chemistry

113

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“…To test whether clathrin-dependent endocytosis of NMDA receptors (Vissel et al, 2001;Nong et al, 2003) is also involved in the 5-HT 1A modulation of NMDAR currents, we dialyzed neurons with a dynamin inhibitory peptide that interferes with the binding of amphiphysin with dynamin and therefore prevents endocytosis through clathrin-coated pits (Grabs et al, 1997;Marks and McMahon, 1998). We found that the effect of 8-OH-DPAT was intact in neurons loaded with the dynamin inhibitory peptide (50 M; 21.5 Ϯ 2.1%; n ϭ 4) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging evidence has suggested that the NMDA receptor is not a static resident in the plasma membrane and may undergo regulated transport to and from the cell surface and lateral diffusion at synaptic and extrasynaptic sites in the plasma membrane (Wenthold et al, 2003;Collingridge et al, 2004). Several mechanisms have been proposed to be important for stabilizing and/or promoting surface NMDA receptor expression, including the PDZ (PSD-95/ Discs large/zona occludens-1) domain-mediated interactions between NR2 subunits and the synaptic scaffolding protein PSD-95 that is regulated by activity-dependent phosphorylation (Roche et al, 2001;Chung et al, 2004;Lin et al, 2004) and tyrosine dephosphorylation of NR1/2A receptors that triggers clathrindependent endocytosis (Vissel et al, 2001). Moreover, it has been found that NR2A and NR2B have distinct endocytic motifs and endocytic sorting, with NR2B undergoing more robust endocytosis than NR2A in mature cultures (Lavezzari et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Yuen¹

2005

Journal of Neuroscience

207

197

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The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT 1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT 1A receptors. This effect of 5-HT 1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signalregulated kinase) abolished the 5-HT 1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT 1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT 1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesinbased dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT 1A -NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.

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“…However, NR1 was not observed to be involved in neuronal protection and neurite outgrowth in the absence of LPS treatment, which may induce not only NR1 expression but also posttranslational modifications such as phosphorylation that modify its function or other factors affected in the presence of LPS (Caudle et al, 2005). Furthermore, the protective effects of NR1 may be activity dependent because membrane depolarization was required to activate NMDAR (Vissel et al, 2001). In addition, a recent study indicated that NR1 interacts with synaptic adhesion-like molecules (SALMs) and is involved in neurite outgrowth (Wang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

Yeh¹,

Hung²,

Gean³

et al. 2008

J. Neurosci.

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Inflammation is involved in some neurodegenerative disorders. NMDA glutamate receptors play an important role in neuronal development. Here, we show that NR1 expression in the cerebral cortex and primary neurons of rats was upregulated after lipopolysaccharide (LPS) treatment. This increase in NR1 expression was considered to be strongly associated with hypoxia-inducible factor-1␣ (HIF-1␣) activation because the treatment of primary neurons with either echinomycin or small interfering RNA (siRNA) targeting HIF-1␣ could block NR1 expression. HIF-1␣ could be induced by an increase in the translational efficiency of the cells. After this, it was transported into the nucleus where it bound to the NR1 promoter and regulated the induction of NR1 transcriptional activity by LPS. LPS injection into the prefrontal cortex caused neuronal death, and this condition was aggravated by intracerebroventricular injection of echinomycin. Furthermore, knockdown of HIF-1␣ and NR1 by the appropriate siRNAs reduced the neurite outgrowth and viability of the primary neurons. These results suggest that NR1 expression is regulated by HIF-1␣ and plays a protective role in neurons during LPS challenge.

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A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux

Cited by 230 publications

References 49 publications

Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

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