The Maternal Transcript for Truncated Voltage-Dependent Ca2+ Channels in the Ascidian Embryo: A Potential Suppressive Role in Ca2+ Channel Expression

Okagaki, Ryugo; Izumi, Hikari; Okada, Toshiaki; Nagahora, Hitoshi; Nakajo, Koichi; Okamura, Yasushi

doi:10.1006/dbio.2000.0119

Cited by 38 publications

(31 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our finding that the majority of Ca V 2.1 transcripts in mature rat Purkinje cells lack the NPencoding exon is in agreement with an earlier prediction (2) and with the isolation of transcripts lacking the NP-encoding exon from mouse Purkinje cells (33,35). The scarcity in rat Purkinje cells of splicing events that introduce a premature stop codon after the NP-encoding exon 31a in some cerebellar transcripts predicts a higher level of Ca V 2.1 protein expression in Purkinje cells than in other cerebellar cells, if the truncated Ca V 2.1 proteins encoded by these transcripts act in a dominant negative manner to inhibit the expression of full-length Ca V 2.1 proteins (12,24,25). A further difference between the cerebellum and Purkinje cells is that, in Purkinje cells, the two splice events at exon 37 (a or b) and the two splice events at exon 44 (inclusion or exclusion) do not occur in all four possible combinations.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing generates a smaller assortment of Ca_V2.1 transcripts in cerebellar Purkinje cells than in the cerebellum

Kanumilli

Tringham

Payne

et al. 2006

Physiological Genomics

View full text Add to dashboard Cite

Alternative splicing generates a smaller assortment of CaV2.1 transcripts in cerebellar Purkinje cells than in the cerebellum. Physiol Genomics 24: 86 -96, 2006. First published November 8, 2005 doi:10.1152/physiolgenomics.00149.2005.-P/Qtype calcium channels control many calcium-driven functions in the brain. The CACNA1A gene encoding the pore-forming CaV2.1 (␣1A) subunit of P/Q-type channels undergoes alternative splicing at multiple loci. This results in channel variants with different phenotypes. However, the combinatorial patterns of alternative splice events at two or more loci, and hence the diversity of CaV2.1 transcripts, are incompletely defined for specific brain regions and types of brain neurons. Using RT-PCR and splice variant-specific primers, we have identified multiple CaV2.1 transcript variants defined by different pairs of splice events in the cerebellum of adult rat. We have uncovered new splice variations between exons 28 and 34 (some of which predict a premature stop codon) and a new variation in exon 47 (which predicts a novel extended COOH-terminus). Single cell RT-PCR reveals that each individual cerebellar Purkinje neuron also expresses multiple alternative CaV2.1 transcripts, but the assortment is smaller than in the cerebellum. Two of these variants encode different extended COOH-termini which are not the same as those previously reported in Purkinje cells of the mouse. Our patch-clamp recordings show that calcium channel currents in the soma and dendrites of Purkinje cells are largely inhibited by a concentration of -agatoxin IVA selective for P-type over Q-type channels, suggesting that the different transcripts may form phenotypic variants of P-type calcium channels in Purkinje cells. These results expand the known diversity of Ca V2.1 transcripts in cerebellar Purkinje cells, and propose the selective expression of distinct assortments of Ca V2.1 transcripts in different brain neurons and species. splice variants; P type; calcium channels; Purkinje neurons 0 VOLTAGE-GATED calcium (Ca 2ϩ ) channels regulate numerous cellular functions, from neuronal electrical activity to intracellular signaling pathways. Diversity of Ca 2ϩ channels in the brain is apparent from the many roles that Ca 2ϩ channels play in different cell types and subcellular compartments (3). The diversity reflects, in part, the existence of nine classes of the pore-forming Ca V (␣1) subunit in the brain and alternative pre-mRNA splicing of the gene encoding each class of Ca V subunit (12, 17). P/Q-type Ca 2ϩ channels control many functions throughout the brain and contain a Ca V 2.1 subunit (also known as ␣ 1A ). However, information about splicing of the CACNA1A gene encoding Ca V 2.1 in different brain regions and neurons is incomplete (2,5,16,30,33,35,37). Augmentation of what is currently known about Ca V 2.1 splicing in the cerebellum and cerebellar Purkinje cells is of particular interest, because P-type currents in Purkinje cells are the prototypical P-type currents against which putative P-type and Q-...

show abstract

Section: Discussionmentioning

confidence: 99%

Alternative splicing generates a smaller assortment of Ca_V2.1 transcripts in cerebellar Purkinje cells than in the cerebellum

Kanumilli

Tringham

Payne

et al. 2006

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…Other less common forms of regulation may exist. In ascidian embryos, a truncated form of L-type Ca 2ϩ channel mRNA is expressed early in development (458) and can suppress expression of the full-length form. The downregulation of this truncated form appears to function as a late, positive regulator of a rapid rise the developmental appearance of the fully functional L-type Ca 2ϩ channel.…”

Section: Relative Timing Differences Of the Development Of Different mentioning

confidence: 99%

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

Moody¹,

Bosma²

2005

Physiological Reviews

340

323

View full text Add to dashboard Cite

At specific stages of development, nerve and muscle cells generate spontaneous electrical activity that is required for normal maturation of intrinsic excitability and synaptic connectivity. The patterns of this spontaneous activity are not simply immature versions of the mature activity, but rather are highly specialized to initiate and control many aspects of neuronal development. The configuration of voltage- and ligand-gated ion channels that are expressed early in development regulate the timing and waveform of this activity. They also regulate Ca2+ influx during spontaneous activity, which is the first step in triggering activity-dependent developmental programs. For these reasons, the properties of voltage- and ligand-gated ion channels expressed by developing neurons and muscle cells often differ markedly from those of adult cells. When viewed from this perspective, the reasons for complex patterns of ion channel emergence and regression during development become much clearer.

show abstract

“…Expression of two-domain isoforms of voltage-gated cation channels including Ca V 1.1, Ca V 1.2, and the Na ϩ channel SCN8A has been found to occur in a number of tissues, in some cases in a developmentally regulated manner (Plummer et al, 1997;Wielowieyski et al, 2001;Okagaki et al, 2001;Ahern et al, 2001;Arikkath et al, 2002). Furthermore, mutations that result in truncations of calcium channel ␣1 subunits can contribute to a number of pathological states.…”

Section: Introductionmentioning

confidence: 99%

Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response

Page

Heblich²,

Davies³

et al. 2004

Journal of Neuroscience

101

View full text Add to dashboard Cite

Expression of the calcium channel Ca V 2.2 is markedly suppressed by coexpression with truncated constructs of Ca V 2.2. Furthermore, a two-domain construct of Ca V 2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca V 2.1 currents. We have now determined the specificity of this effect, identified a potential mechanism, and have shown that such constructs also inhibit endogenous calcium currents when transfected into neuronal cell lines. Suppression of calcium channel expression requires interaction between truncated and full-length channels, because there is inter-subfamily specificity. Although there is marked cross-suppression within the Ca V 2 calcium channel family, there is no cross-suppression between Ca V 2 and Ca V 3 channels. The mechanism involves activation of a component of the unfolded protein response, the endoplasmic reticulum resident RNA-dependent kinase (PERK), because it is inhibited by expression of dominant-negative constructs of this kinase. Activation of PERK has been shown previously to cause translational arrest, which has the potential to result in a generalized effect on protein synthesis. In agreement with this, coexpression of the truncated domain I of Ca V 2.2, together with full-length Ca V 2.2, reduced the level not only of Ca V 2.2 protein but also the coexpressed ␣2␦-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca V 2.2 currents and also reduced the expression level of both Ca V 2.2 and ␣2␦-2 protein. We propose that voltage-gated calcium channels represent a class of difficult-to-fold transmembrane proteins, in this case misfolding is induced by interaction with a truncated cognate Ca V channel. This may represent a mechanism of pathology in episodic ataxia-2.

show abstract

The Maternal Transcript for Truncated Voltage-Dependent Ca2+ Channels in the Ascidian Embryo: A Potential Suppressive Role in Ca2+ Channel Expression

Cited by 38 publications

References 61 publications

Alternative splicing generates a smaller assortment of Ca_V2.1 transcripts in cerebellar Purkinje cells than in the cerebellum

Alternative splicing generates a smaller assortment of Ca_V2.1 transcripts in cerebellar Purkinje cells than in the cerebellum

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response

Contact Info

Product

Resources

About