Control of alternative pre-mRNA splicing by Ca++ signals

Xie, Jiuyong

doi:10.1016/j.bbagrm.2008.01.003

Cited by 40 publications

(40 citation statements)

References 221 publications

(293 reference statements)

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“…Alternative splicing can be regulated by external cues resulting, for example, in changes of intracellular Ca 2+ (Xie 2008;Stamm 2002). Similarly, editing by the editases ADAR1 and 2 can be reprogrammed (Schmauss 2005).…”

Section: The Modulatory Lbd Dimer Interfacementioning

confidence: 97%

AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

Sukumaran

Penn

Greger

2012

Synaptic Plasticity

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Glutamate-gated ion channels (iGluRs) predominantly operate as heterotetramers to mediate excitatory neurotransmission at glutamatergic synapses. The subunit composition of the receptors determines their targeting to synaptic sites and signalling properties and is therefore a fundamental parameter for neuronal computations. iGluRs assemble as obligatory or preferential heteromers; the mechanisms underlying this selective assembly are only starting to emerge. Here we review recent work in the field and provide an in-depth update on atomic determinants in the assembly domains, which have been facilitated by recent advances in iGluR structural biology. We also discuss the role of alternative RNA processing in the ligand-binding domain, which modulates a central subunit interface and has the capacity to modulate receptor formation in response to external cues. Finally, we review the emerging physiological significance of signalling via distinct iGluR heterotetramers and provide examples of how recruitment of functionally diverse receptors modulates excitatory neurotransmission under physiological and pathological conditions.

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Section: The Modulatory Lbd Dimer Interfacementioning

confidence: 97%

AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

Sukumaran

Penn

Greger

2012

Synaptic Plasticity

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“…Membrane depolarization and activated Ca 2ϩ /calmodulindependent protein kinase IV (CaMKIV) control the alternative inclusion of many exons (11,34), including stress axis-regulated exon (STREX) of the Ca 2ϩ /voltage-sensitive Slo potassium channel gene (35,36). This control is through distinct CaMKIV-responsive RNA elements (CaRRE1 and CaRRE2) or the UAGG motif (11, 16 -19).…”

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confidence: 99%

The Heterogeneous Nuclear Ribonucleoprotein L Is an Essential Component in the Ca2+/Calmodulin-dependent Protein Kinase IV-regulated Alternative Splicing through Cytidine-Adenosine Repeats

Yan

Liu

et al. 2009

Journal of Biological Chemistry

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The regulation of gene expression through alternative pre-mRNA splicing is common in metazoans and is often controlled by intracellular signaling pathways that are important in cell physiology. We have shown that the alternative splicing of a number of genes is controlled by membrane depolarization and Ca 2؉ /calmodulin-dependent protein kinase IV (CaMKIV) through CaMKIV-responsive RNA elements (CaRRE1 and CaRRE2); however, the trans-acting factors remain unknown. Here we show that the heterogeneous nuclear ribonucleoprotein (hnRNP) L is a CaRRE1 binding factor in nuclear extracts. An hnRNP L high affinity CA (cytidine-adenosine) repeat element is sufficient to mediate CaMKIV and hnRNP L repression of splicing in a location (3-splice site proximity)-dependent way. Depletion of hnRNP L by RNA interference followed by rescue with coexpressed exogenous hnRNP L demonstrates that hnRNP L mediates the CaMKIV-regulated splicing through CA repeats in heterologous contexts. Depletion of hnRNP L also led to increased inclusion of the stress axis-regulated exon and a CA repeat-harboring exon under depolarization or with activated CaMKIV. Moreover, hnRNP L binding to CaRRE1 was increased by CaMKIV and, conversely, was reduced by pretreatments with protein phosphatases. Therefore, hnRNP L is an essential component of CaMKIV-regulated alternative splicing through CA repeats, with its phosphorylation likely playing a critical role.Alternative pre-mRNA splicing allows the generation of multiple protein isoforms from a single transcript, contributing greatly to proteomic complexity (1-6). It is essential for normal cell function, and aberrant splicing is implicated in the development of human genetic diseases (7,8). Many alternative splicing events can be regulated by cell signals and may play important roles in cell physiology (9 -11). However, little is known of the essential molecular components between cell signals and the splicing machinery.Alternative splicing in mammalian systems is often controlled by multiple cis-acting regulatory elements in introns and exons (1, 12). These elements are mostly bound by transacting protein factors and in some cases by small nucleolar RNA (13) or form RNA secondary structures (14). The transacting factors are thought to control the assembly of constitutive splicing components to the target splice sites. For cell signal control of alternative splicing, RNA elements and trans-acting factors have been identified in several systems (9,10,(15)(16)(17)(18)(19)(20)(21)(22)(23).CA repeats are the most abundant and highly polymorphic dinucleotide repeats in the human genome. They are widely used in genetic linkage analyses (24), and their instability is characteristic of the mutator phenotype of cells defective in DNA repair genes (25). Recent studies indicate that long (Ն19 repeats) or short clustered CA repeats in downstream introns are constitutive enhancers or repressors depending on their proximity to the 5Ј-splice site (26,27). These effects are mediated by the heterogeneous nuclear ribonuc...

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“…Context Dependence of Cell Signal-regulated Alternative Splicing-Context dependence of pre-mRNA elements on splicing has been observed in many cases (5,(17)(18)(19), but opposite effects of a kinase in splicing through the same element in different minigenes have not been observed. We have shown here that, through the CaRRE1, CaMKIV inhibits exon inclusion in one minigene, DUP175ST (6), but promotes exon inclusion in another minigene, 33SB-CaRRE1 (Fig.…”

Section: Several Considerations About the In Vivo Selectionmentioning

confidence: 99%

“…Alternative splicing in mammalian systems is controlled by multiple intronic and exonic regulatory elements called intronic or exonic splicing enhancers or silencers (1,16,17). The effect of a particular element can be either enhancer or silencer depending on its surrounding context in the pre-mRNA (5,(17)(18)(19). RNA elements that mediate cell signalregulated splicing have also been isolated.…”

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confidence: 99%

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In Vivo Selection of Kinase-responsive RNA Elements Controlling Alternative Splicing

Liu

et al. 2009

Journal of Biological Chemistry

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Alternative pre-mRNA splicing is often controlled by cell signals, for example, those activating the cAMP-dependent protein kinase (PKA) or the Ca 2؉ /calmodulin-dependent protein kinase IV (CaMKIV). We have shown that CaMKIV regulates alternative splicing through short CA repeats and hnRNP L. Here we use a splicing reporter that shows PKA/CaMKIV promotion of exon inclusion to select from exons containing random 13-nt sequences for RNA elements responsive to the kinases in cultured cells. This selection not only identified both PKA-and CaMKIV-responsive elements that are similar to the CaMKIVresponsive RNA element 1 (CaRRE1) or CA repeats, but also A-rich elements not previously known to respond to these kinases. Consistently, hnRNP L is identified as a factor binding the CA-rich elements. Analyses of the motifs in the highly responsive elements indicate that they are indeed critical for the kinase effect and are enriched in alternative exons. Interestingly, a CAAAAAA motif is sufficient for the PKA/CaMKIVregulated splicing of the exon 16 of the CaMK kinase ␤1 (CaMKK2) transcripts, implying a role of this motif in signaling cross-talk or feedback regulation between these kinases through alternative splicing. Therefore, these experiments identified a group of RNA elements responsive to PKA and CaMKIV from in vivo selection. This also provides an approach for selecting RNA elements similarly responsive to other cell signals controlling alternative splicing.Alternative pre-mRNA splicing is a common means of gene expression regulation in metazoans (1, 2). The expression of splice variants is controlled not only in a tissue-, sex-, or developmental stage-specific way but also in response to stimulation of particular protein kinases by extracellular factors (3-5).Many extracellular factors, including neurotransmitters and hormones, activate calcium and/or cAMP signals and downstream protein kinases. Besides membrane depolarization and the calcium/calmodulin-dependent protein kinase IV (CaMKIV) 4 (5-11), the cAMP-dependent protein kinase A (PKA) has also been implicated in the regulation of alternative splicing. For example, dopamine induces alternative splicing in striatal neurons through the dopamine receptor that activates the PKA pathway (12-14). PKA phosphorylates and colocalizes with arginine/serine-rich (SR) splicing factors and regulates alternative splicing of an E1A minigene (15). Alternative splicing in mammalian systems is controlled by multiple intronic and exonic regulatory elements called intronic or exonic splicing enhancers or silencers (1,16,17). The effect of a particular element can be either enhancer or silencer depending on its surrounding context in the pre-mRNA (5,(17)(18)(19). RNA elements that mediate cell signalregulated splicing have also been isolated. These elements include the A-rich element in the CD44 exon 5, the CaMKIVresponsive RNA elements (CaRRE1 and CaRRE2) in the STREX (stress axis-regulated exon) of Slo and exons 5 and 21 of the NMDAR1 (N-methyl-D-aspartic acid receptor, type I) ...

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Control of alternative pre-mRNA splicing by Ca++ signals

Cited by 40 publications

References 221 publications

AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

The Heterogeneous Nuclear Ribonucleoprotein L Is an Essential Component in the Ca2+/Calmodulin-dependent Protein Kinase IV-regulated Alternative Splicing through Cytidine-Adenosine Repeats

In Vivo Selection of Kinase-responsive RNA Elements Controlling Alternative Splicing

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