Modulation of NMDA receptors in the cerebellum. 1. Properties of the NMDA receptor that modulate its function

Llansola, Marta; Sánchez-Pérez, Ana; Cauli, Omar; Felipo, Vicente

doi:10.1080/14734220510007996

Cited by 63 publications

(46 citation statements)

References 47 publications

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“…This slow time course of most splicing responses is compatible with longer-term changes in neuronal activity, such as circadian modulation of excitation, or circuit consolidation during development. Many splicing events, including NR1 exon 5, are seen to change during critical periods of circuit refinement in postnatal development, or in response to chronic stimuli such as kindling or other induced seizures in adult animals (Kamphuis et al 1992;Laurie and Seeburg 1994;Kraus et al 1996;Wang and Grabowski 1996;Rafiki et al 1998;Ying et al 1998;Daoud et al 1999;Hoffmann et al 2000;Musshoff et al 2000;Yin et al 2001;Bottai et al 2002;Llansola et al 2005;Jaekel et al 2006). The role of Fox-mediated alternative splicing in modulating changes in membrane physiology during these processes thus invites further study.…”

Section: Discussionmentioning

confidence: 99%

“…Ion channel mRNAs and other transcripts affecting membrane activity also often contain exons whose splicing responds to chronic depolarizing stimuli McKee et al 2007). Two examples of depolarization and CaM kinase IV (CAMKIV)-dependent splicing are exons 5 and 21 in the NMDA receptor 1 transcript (NR1), a glutamate receptor that modulates processes of synaptic plasticity (Zukin and Bennett 1995;Cull-Candy et al 2001;Llansola et al 2005). Alternative exon 5 encodes the N1 cassette in the extracellular domain that regulates agonist binding and other pharmacological properties of the receptor (Traynelis et al 1995;Rumbaugh et al 2000).…”

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confidence: 99%

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An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

Lee¹,

Tang²,

Black³

2009

Genes Dev.

142

151

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Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in the initial phase of chronic depolarization. The splicing of many neuronal transcripts is also regulated by members of the Fox (Feminizing gene on X) protein family, and these Fox targets are also often proteins affecting synaptic activity. We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated in a variety of neurological diseases, can counteract the effects of chronic depolarization on splicing. We find that exon 19 of Fox-1 is itself repressed by depolarization. Fox-1 transcripts missing exon 19 encode a nuclear isoform of Fox-1 that progressively replaces the cytoplasmic Fox-1 isoform as cells are maintained depolarizing media. The resulting increase in nuclear Fox-1 leads to the reactivation of many Fox-1 target exons, including exon 5 of the NMDA receptor 1, that were initially repressed by the high-KCl medium. These results reveal a novel mechanism for the slow modulation of splicing as cells adapt to chronic stimuli: The subcellular localization of a splicing regulator is controlled through its own alternative splicing. Alternative pre-mRNA splicing is an important mechanism for controlling gene expression in metazoan organisms. Changes in splice site or exon usage frequently determine the function of a gene product or eliminate its expression (Black 2003;Matlin et al. 2005;Blencowe 2006). The best understood systems of splicing regulation are those modulated by cell type, where stable differences in pre-mRNA-binding protein expression determine a splicing choice. However, splicing is also dynamically regulated by external stimuli and growth conditions. Most cellular signaling pathways that alter gene transcription also alter groups of alternative exons (Shin and Manley 2004;Blaustein et al. 2007;Stamm 2008). In some cases, these responses have been traced to particular regulatory elements in the pre-mRNA, to post-translational modifications of splicing regulators, or to changes in transcriptional control. However, the mechanisms that allow the splicing machinery to respond to dynamic stimuli are not well understood.A particularly interesting regulatory mechanism in excitable cells is their response to membrane depolarization. Depolarization-induced changes in neuronal transcription are well studied and involve the activation of CaM kinase and other signaling pathways to induce transcription of both rapid primary response genes and more slowly developing secondary responses (Flavell and Greenberg 2008;Greer and Greenberg 2008). These transcriptional programs play important roles in neuronal plasticity and modulating synaptic activation. Ion channel mRNAs and other transcripts affecting membrane activity also often contain exons whose splicing responds to chronic depolar...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

Lee¹,

Tang²,

Black³

2009

Genes Dev.

142

151

View full text Add to dashboard Cite

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“…(including PKA, CAMK II, and CK2) (Llansola et al 2005) and also Tyr phosphorylation of NR2 subunits mediated by members of the SRC family (Salter and Kalia 2004). The reduced NMDA receptor function in JIP1/2-deficient neurons might therefore be mediated by altered regulatory phosphorylation of the NMDA receptor.…”

Section: Jip-deficient Neurons Exhibit Defects In Nmda Receptor Tyrosmentioning

confidence: 99%

Requirement of JIP scaffold proteins for NMDA-mediated signal transduction

Kennedy¹,

Martin²,

Ehrhardt³

et al. 2007

Genes Dev.

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JIP scaffold proteins are implicated in the regulation of protein kinase signal transduction pathways. To test the physiological role of these scaffold proteins, we examined the phenotype of compound mutant mice that lack expression of JIP proteins. These mice were found to exhibit severe defects in N-methyl-D-aspartic acid (NMDA) receptor function, including decreased NMDA-evoked current amplitude, cytoplasmic Ca ++ , and gene expression. The decreased NMDA receptor activity in JIP-deficient neurons is associated with reduced tyrosine phosphorylation of NR2 subunits of the NMDA receptor. JIP complexes interact with the SH2 domain of cFyn and may therefore promote tyrosine phosphorylation and activity of the NMDA receptor. We conclude that JIP scaffold proteins are critically required for normal NMDA receptor function.[Keywords: JIP; JNK; scaffold protein; signal transduction] Supplemental material is available at http://www.genesdev.org.

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“…Each AMPAR subunit can be N-glyco- sylated at 4-6 different sites located in the extracellular domains of the protein facilitating its maturation, protecting the receptor from proteolytic degradation and affecting receptor current amplitudes. However, the lack of N-glycosylation does not affect AMPAR subunit synthesis, assembly, or trafficking [34].…”

Section: Sialylationmentioning

confidence: 99%

“…Another factor modulating NMDARs function is the synaptic localization: the trafficking and clustering of NMDARs is modulated by phosphorylation and by interaction with other proteins [16,34]. Exploration in spatial memory formation in a radial arm maze has shown that spatial learning induced tyrosine phosphorylation of NR2B in the hippocampus [9].…”

Section: Neurotransmitter Receptors/trafficking Systemmentioning

confidence: 99%

The role of post‐translational modifications for learning and memory formation

2008

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Learning and memory depend on molecular mechanisms involving the protein machinery. Recent evidence proposes that post-translational modifications (PTMs) play a major role in these cognitive processes. PTMs including phosphorylation of serine, threonine, and tyrosine are already well-documented to play a role for synaptic plasticity of the brain, neurotransmitter release, vesicle trafficking and synaptosomal or synaptosomal-associated proteins are substrates of a series of specific protein kinases and their counterparts, protein phosphatases. But protein phosphorylation is only one out of many possible PTMs and first work shows a role of palmitoylation as well as glycosylation for proteins involved in memory formation. Recent technology may now allow reliable detection and even quantification of PTMs of proteins involved in the cognitive system. This will contribute to the understanding of mechanisms for learning and memory formation at the chemical level and has to complement determination of protein levels and indeed determination of protein expression per se generates limited information. The many other PTMs expected including protein nitrosylation and alkylation will even represent targets for pharmacological interventions but in turn increase the complexity of the system. Nevertheless, determination of the presence and the function of PTMs is mandatory and promising cognitive research at the protein chemical level.

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Modulation of NMDA receptors in the cerebellum. 1. Properties of the NMDA receptor that modulate its function

Cited by 63 publications

References 47 publications

An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

Requirement of JIP scaffold proteins for NMDA-mediated signal transduction

The role of post‐translational modifications for learning and memory formation

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