Alternative Splicing Matters: N-Type Calcium Channels in Nociceptors

Lipscombe, Diane; Raingo, Jesica

doi:10.4161/chan.4809

Cited by 25 publications

(23 citation statements)

References 14 publications

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“…These ion channel targets point to the importance of examining the localization of Fox-1 and the splicing of Fox-1 target exons in settings that allow measurements of membrane physiology. Individual alternative protein isoforms of ion channels and neurotransmitter receptors have been shown to affect various types of long-term potentiation, and also to adapt physiological responses to specific cell types or conditions (Xie and McCobb 1998;Beffert et al 2005;Huang et al 2005;Lipscombe 2005;Li et al 2007;Lipscombe and Raingo 2007;Raingo et al 2007). However, changes in spliced isoform ratios depend on rates of mRNA decay, and are usually measured over the course of hours in response to chronic stimuli such as depolarizing media or drugs that block or stimulate synaptic activity.…”

Section: Discussionmentioning

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.

144

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%

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

Lee¹,

Tang²,

Black³

2009

Genes Dev.

144

151

View full text Add to dashboard Cite

show abstract

“…24,83 However, exon37a appears to confer a greater susceptibility to voltage-independent inhibition of N-type channel currents through a mechanism involving Gi/o subunits and kinase-dependent phosphorylation. 9,24 A tyrosine encoded within exon37a, but not exon37b, acts as a molecular switch in controlling N-type channel current density and voltage-independent inhibition that ultimately leads to modulation of nociception. 24 Furthermore, exon37a regulates the extent of μ-opioid receptor-mediated inhibition of N-type channels, and the absence of exon37a results in reduced morphine-induced analgesia without affecting basal response to noxious thermal stimuli.…”

Section: N-type Voltage-gated Calcium Channelsmentioning

confidence: 99%

“…1 This subunit is also subjected to alternative splicing. [3][4][5][6][7][8][9][10][11] The α 1 -subunit consists of four homologous domains (I-IV), each having six transmembrane helices (S1 through S6), which together form the calcium conduction pore, voltage sensors and gating apparatus. 12 The S4 transmembrane domain contains positive charged amino acids for voltage sensing.…”

Section: Introductionmentioning

confidence: 99%

Calcium channel functions in pain processing

Park¹,

Luo²

2010

Channels

122

103

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“…The variety of calcium channel types required to support such diversity of function is achieved by both extensive alternative splicing of subunit genes and the various combinations with which the subunits coassemble (Bourinet et al 1999;Krovetz et al 2000;Lipscombe 2005;Lipscombe and Raingo 2007;Lipscombe et al 2013), the result being the generation of multiple channels with each showing finely tuned biophysical properties tailored to cell-and network-specific roles. Here, we focus on two functions that, in particular, have implications for seizure gen-eration, their presynaptic involvement in neurotransmitter release, and their role in burst firing.…”

Section: Physiological Roles Of Calcium Channels In Neuronsmentioning

confidence: 99%

The Role of Calcium Channels in Epilepsy

Rajakulendran

Hanna

2016

Cold Spring Harb Perspect Med

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A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of seizures have raised expectations of a causal role of calcium channels in the polygenic inheritance of idiopathic epilepsy. In this review, we consider how genetic variation in neuronal VGCCs may influence the development of epilepsy.

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Alternative Splicing Matters: N-Type Calcium Channels in Nociceptors

Cited by 25 publications

References 14 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

Calcium channel functions in pain processing

The Role of Calcium Channels in Epilepsy

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