CACNA1E

Gene Summary

Gene:CACNA1E; calcium voltage-gated channel subunit alpha1 E
Aliases: BII, CACH6, gm139, Cav2.3, EIEE69, CACNL1A6
Location:1q25.3
Summary:Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:voltage-dependent R-type calcium channel subunit alpha-1E
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CACNA1E (cancer-related)

Li Y, Bai W, Zhang X
Identifying heterogeneous subtypes of gastric cancer and subtype‑specific subpaths of microRNA‑target pathways.
Mol Med Rep. 2018; 17(3):3583-3590 [PubMed] Free Access to Full Article Related Publications
The present study aimed to classify gastric cancer (GC) into subtypes and to screen the subtype‑specific genes, their targeted microRNAs (miRNAs) and enriched pathways to explore the putative mechanism of each GC subtypes. The GSE13861 data set was downloaded from the Gene Expression Omnibus and used to screen differential expression genes (DEGs) in GC samples based on the detection of imbalanced differential signal algorithm. The specific genes in each subtype were identified with the cut‑off criterion of U>0.04, pathway enrichment analysis was performed and the subtype‑specific subpaths of miRNA‑target pathway were determined. A total of 1,263 DEGs were identified in the primary gastric adenocarcinoma (PGD) samples, which were subsequently divided into four subtypes, according to the hierarchy cluster analysis. Identification of the subpaths of each subtype indicated that the subpath related to subtype 1 was miRNA (miR)‑202/calcium voltage‑gated channel subunit α1 (CACNA1E)/type II diabetes mellitus. The nuclear factor‑κB signaling pathway was the most significantly specific pathway and subpath identified for subtype 2, which was regulated by miR‑338‑targeted suppression of C‑C motif chemokine ligand 21 (CCL21). For subtype 3, significant related pathways included ubiquitin‑mediated proteolysis and proteasome, and the important subpath was miR‑146B/proteasome 26S subunit, non‑ATPase 3 (PSMD3)/proteasome; focal adhesion was the significant pathway indicated for subtype 4, and the subpaths were miR‑34A/vinculin (VCL)/focal adhesion and miR‑34C/VCL/focal adhesion. In addition, Helicobacter pylori infection was higher in GC subtype 1 than in other subtypes. Specific genes, such as CACNA1E, CCL21, PSMD3 and VCL, may be used as potential feature genes to identify different subtypes of GC, and their associated subpaths may partially explain the pathogenetic mechanism of each GC subtype.

Gandla J, Lomada SK, Lu J, et al.
miR-34c-5p functions as pronociceptive microRNA in cancer pain by targeting Cav2.3 containing calcium channels.
Pain. 2017; 158(9):1765-1779 [PubMed] Free Access to Full Article Related Publications
Pathophysiological mechanisms underlying pain associated with cancer are poorly understood. microRNAs (miRNAs) are a class of noncoding RNAs with emerging functional importance in chronic pain. In a genome-wide screen for miRNAs regulated in dorsal root ganglia (DRG) neurons in a mouse model of bone metastatic pain, we identified miR-34c-5p as a functionally important pronociceptive miRNA. Despite these functional insights and therapeutic potential for miR-34c-5p, its molecular mechanism of action in peripheral sensory neurons remains unknown. Here, we report the identification and validation of key target transcripts of miRNA-34c-5p. In-depth bioinformatics analyses revealed Cav2.3, P2rx6, Oprd1, and Oprm1 as high confidence putative targets for miRNA-34c-5p. Of these, canonical and reciprocal regulation of miR-34c-5p and Cav2.3 was observed in cultured sensory neurons as well as in DRG in vivo in mice with cancer pain. Coexpression of miR-34c-5p and Cav2.3 was observed in peptidergic and nonpeptidergic nociceptors, and luciferase reporter assays confirmed functional binding of miR-34c-5p to the 3' UTR of Cav2.3 transcripts. Importantly, knocking down the expression of Cav2.3 specifically in DRG neurons led to hypersensitivity in mice. In summary, these results show that Cav2.3 is a novel mechanistic target for a key pronociceptive miRNA, miR-34c-5p, in the context of cancer pain and indicate an antinociceptive role for Cav2.3 in peripheral sensory neurons. The current study facilitates a deeper understanding of molecular mechanisms underlying cancer pain and suggests a potential for novel therapeutic strategies targeting miR-34c-5p and Cav2.3 in cancer pain.

Zhang X, Zhang M, Hou Y, et al.
Single-cell analyses of transcriptional heterogeneity in squamous cell carcinoma of urinary bladder.
Oncotarget. 2016; 7(40):66069-66076 [PubMed] Free Access to Full Article Related Publications
Cell-to-cell expression heterogeneity within a single tumor is a common phenotype among various cancer types including squamous cell carcinoma. To further study the fundamentals and importance of heterogeneity of cell functions and its potential mechanisms, we performed single-cell RNA-seq (scRNA-seq) on human squamous cell carcinoma of the bladder (SCCB) and its corresponding physiologically normal epithelia. Extensive differentially expressed genes were uncovered by comparing cancer and normal single cells, which were preferentially enriched in cancer-correlated pathways, such as p53 signaling and bladder cancer pathway. Furthermore, the most diversely expressed genes were particularly enriched in MAPK signaling pathway, such as CACNG4, CACNA1E and CACNA1H, which involve in cancer evolution and heterogeneity formation. Co-expression network and hub-gene analyses revealed several remarkable "hub genes" of each regulatory module. Some of them are cancer related, such as POU2F3, NKD1 and CYP2C8, while LINC00189, GCC2 and OR9Q1 genes are rarely reported in human diseases. The genes within an interesting module are highly correlated with others, which could be treated as potential targets for SCCB patients. Our findings have fundamental implications for SCCB biology and therapeutic strategies.

Yu XJ, Yang MJ, Zhou B, et al.
Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer.
EBioMedicine. 2015; 2(6):583-90 [PubMed] Free Access to Full Article Related Publications
Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G → A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001). We found 167 genes (including TP53, RYR2, KRAS, CACNA1E) which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime benzo(a)pyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure-genomic mutation relationship at a large scale.

Kang G, Yun H, Sun CH, et al.
Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors.
Oncotarget. 2016; 7(6):6538-51 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. We sequenced nine exomes and transcriptomes, and two genomes of GISTs for integrated analyses. We detected 306 somatic variants in nine GISTs and recurrent protein-altering mutations in 29 genes. Transcriptome sequencing revealed 328 gene fusions, and the most frequently involved fusion events were associated with IGF2 fused to several partner genes including CCND1, FUS, and LASP1. We additionally identified three recurrent read-through fusion transcripts: POLA2-CDC42EP2, C8orf42-FBXO25, and STX16-NPEPL1. Notably, we found intragenic deletions in one of three exons of the VHL gene and increased mRNAs of VEGF, PDGF-β, and IGF-1/2 in 56% of GISTs, suggesting a mechanistic link between VHL inactivation and overexpression of hypoxia-inducible factor target genes in the absence of hypoxia. We also identified copy number gain and increased mRNA expression of AMACR, CRIM1, SKP2, and CACNA1E. Mapping of copy number and gene expression results to the KEGG pathways revealed activation of the JAK-STAT pathway in small intestinal GISTs and the MAPK pathway in wild-type GISTs. These observations will allow us to determine the genetic basis of GISTs and will facilitate further investigation to develop new therapeutic options.

Nitert MD, Nagorny CL, Wendt A, et al.
CaV1.2 rather than CaV1.3 is coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells.
J Mol Endocrinol. 2008; 41(1):1-11 [PubMed] Related Publications
In clonal beta-cell lines and islets from different species, a variety of calcium channels are coupled to glucose-stimulated insulin secretion. The aim of this study was to identify the voltage-gated calcium channels that control insulin secretion in insulinoma (INS)-1 832/13 cells. The mRNA level of Ca(V)1.2 exceeded that of Ca(V)1.3 and Ca(V)2.3 two-fold. Insulin secretion, which rose tenfold in response to 16.7 mM glucose, was completely abolished by 5 microM isradipine that blocks Ca(V)1.2 and Ca(V)1.3. Similarly, the increase in intracellular calcium in response to 15 mM glucose was decreased in the presence of 5 microM isradipine, and the frequency of calcium spikes was decreased to the level seen at 2.8 mM glucose. By contrast, inhibition of Ca(V)2.3 with 100 nM SNX-482 did not significantly affect insulin secretion or intracellular calcium. Using RNA interference, Ca(V)1.2 mRNA and protein levels were knocked down by approximately 65% and approximately 34% respectively, which reduced insulin secretion in response to 16.7 mM glucose by 50%. Similar reductions in calcium currents and cell capacitance were seen in standard whole-cell patch-clamp experiments. The remaining secretion of insulin could be reduced to the basal level by 5 microM isradipine. Calcium influx underlying this residual insulin secretion could result from persisting Ca(V)1.2 expression in transfected cells since knock-down of Ca(V)1.3 did not affect glucose-stimulated insulin secretion. In summary, our results suggest that Ca(V)1.2 is critical for insulin secretion in INS-1 832/13 cells.

Li Y, Ganta S, Cheng C, et al.
FSH stimulates ovarian cancer cell growth by action on growth factor variant receptor.
Mol Cell Endocrinol. 2007; 267(1-2):26-37 [PubMed] Free Access to Full Article Related Publications
A number of FSH receptor (FSH-R) isoforms with distinct structural motifs and signaling paradigms have been described, including a single transmembrane domain variant that functions as a growth factor type receptor (FSH-R3). This study tested the hypothesis that FSH can stimulate ovarian cancer cell proliferation by acting on FSH-R3, using the tumorigenic mouse ovarian surface epithelial cell (MOSEC) line ID8. FSH enhanced ID8 proliferation in a concentration-dependent fashion. Moreover, FSH-treatment of ID8 elicited intracellular events consistent with activation of FSH-R3 and distinct from those associated with activation of the canonical G-protein coupled FSH-R isoform (FSH-R1). Specifically, the FSH-R3 signaling pathway included cAMP-independent activation of ERK downstream of an SNX-482 sensitive component likely to be the Cav2.3 calcium channel. Northern analysis using probes specific for exons 7 and 11 of FSH-R identified consistently only one 1.9kb transcript. Immunoblot analysis confirmed expression of FSH-R3 but not FSHR-1 in ID8. Together, these data suggest that FSH-R3 signaling promotes proliferation of ovarian cancer cells.

Natrajan R, Little SE, Reis-Filho JS, et al.
Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms' tumors.
Clin Cancer Res. 2006; 12(24):7284-93 [PubMed] Related Publications
PURPOSE: The most well established molecular markers of poor outcome in Wilms' tumor are loss of heterozygosity at chromosomes 1p and/or 16q, although to date no specific genes at these loci have been identified. We have previously shown a link between genomic gain of chromosome 1q and tumor relapse and sought to further elucidate the role of genes on 1q in treatment failure.
EXPERIMENTAL DESIGN: Microarray-based comparative genomic hybridization identified a microamplification harboring a single gene (CACNA1E) at 1q25.3 in 6 of 76 (7.9%) Wilms' tumors, correlating with a shorter relapse-free survival (P = 0.0044, log-rank test). Further characterization of this gene was carried out by measuring mRNA and protein expression as well as stable transfection of HEK293 cells.
RESULTS: Overexpression of the CACNA1E transcript was associated with DNA copy number (P = 0.0204, ANOVA) and tumor relapse (P = 0.0851, log-rank test). Immunohistochemistry against the protein product Ca(V)2.3 revealed expression localized to the apical membrane in the distal tubules of normal kidney but not to the metanephric blastemal cells of fetal kidney from which Wilms' tumors arise. Nuclear localization in 99 of 160 (61.9%) Wilms' tumor cases correlated with a reduced relapse-free survival, particularly in cases treated with preoperative chemotherapy (P = 0.009, log-rank test). Expression profiling of stably transfected HEK293 cells revealed specific up-regulation of the immediate early response genes EGR1/EGR2/EGR3 and FOS/FOSB, mediated by activation of the MEK/ERK5/Nur77 pathway.
CONCLUSIONS: These data identify a unique genetic aberration with direct clinical relevance in Wilms' tumor relapse and provide evidence for a potential novel mechanism of treatment resistance in these tumors.

Mergler S, Strauss O, Strowski M, et al.
Insulin-like growth factor-1 increases intracellular calcium concentration in human primary neuroendocrine pancreatic tumor cells and a pancreatic neuroendocrine tumor cell line (BON-1) via R-type Ca2+ channels and regulates chromogranin a secretion in BON-1 cells.
Neuroendocrinology. 2005; 82(2):87-102 [PubMed] Related Publications
Insulin-like growth factor 1 (IGF-1) is a potent mitogenic and secretory factor that acts on voltage operated Ca(2+) channels (VOCCs). VOCCs are categorized into L-type channels (Ca(V)1.1-1.4), P/Q-type channels (Ca(V)2.1), N-type channels (Ca(V)2.2), R-type channels (Ca(V)2.3), and T-type channels (Ca(V)3.1-3.3). Aside from regulating membrane excitability, VOCCs influence chromogranin A (CgA) secretion in neuroendocrine tumor (NET) cells. It is not known, whether VOCCs play a role in the IGF-1-dependent regulation of CgA secretion in NET cells. We therefore studied the effects of IGF-1 on individual VOCC subtypes and characterized their role in mediating IGF-1-dependent regulation of CgA secretion in NET cells. Using specific modulators of VOCC subtypes, we identified the functional expression of L-, N-, P/Q- and R-type channels in primary as well as permanent models of NET. The IGF-1-induced intracellular Ca(2+) increase in NET cells was mainly due to the activation of R-type channel activity. The effects on intracellular calcium, observed in whole-cell patch-clamp recordings and fluorescence imaging, were partially blocked by the specific R-type channel blocker SNX-482 and antisense oligonucleotides against the alpha(1) subunit of this channel. IGF-1 potently induced CgA secretion. The effect of IGF-1 was reduced by both, inhibition of R-type channel activity and a reduction of R-type channel expression using antisense oligonucleotides. Since R-type channels exist in NET cells and couple to both, IGF-1 receptor signaling as well as CgA secretion, pharmacological interference with R-type channels may represent a new therapeutic option by blocking Ca(2+) signaling thereby abrogating IGF-1-dependent hypersecretion in NET disease.

Mergler S, Wiedenmann B, Prada J
R-type Ca(2+)-channel activity is associated with chromogranin A secretion in human neuroendocrine tumor BON cells.
J Membr Biol. 2003; 194(3):177-86 [PubMed] Related Publications
This electrophysiological study was undertaken to investigate the role of voltage-operated Ca(2+) channels (VOCCs) in cultivated human neuroendocrine tumor (NET) cells. Patch-clamp techniques, measurements of intracellular Ca(2+) ([Ca(2+)](i)), and secretion analysis were performed using cultured human NET BON cells. Ba(2+) inward currents through R-type channels (Ca(V)2.3) were measured and identified by SNX-482 (10 n M), a novel voltage-sensitive R-type Ca(2+) channel antagonist. In the presence of nifedipine (5 micro M), omega-Conotoxin GVIA (100 n M) and omega-Agatoxin IVA (20 n M), R-type channel currents were also detectable. Release of Ca(2+) from intracellular Ca(2+) stores by intracellular application of inositol-1,4,5-trisphosphate (InsP(3); 10 micro M) via the patch pipette during whole-cell configuration as well as induction of capacitative Ca(2+) entry (CCE), a passive maneuver to release Ca(2+) from intracellular Ca(2+) stores, led to an increase in [Ca(2+)](i). This effect could be reduced by SNX-482 (20 n M). In addition, SNX-482 (25 n M) also decreased chromogranin A (CgA) secretion, whereas omega-Conotoxin GVIA (500 n M) and nifedipine (5 micro M) failed to reduce CgA secretion. We conclude that these data reveal neuronal R-type channel activity (Ca(V)2.3), for the first time associated with CgA secretion in BON cells. Influx of Ca(2+) by activation of R-type channels may lead to an increase of intracellular Ca(2+), which stimulates CgA secretion. Thus, R-type channels could play an important role in certain clinical characteristics of NETs, such as the hypersecretion syndrome.

Pereverzev A, Vajna R, Pfitzer G, et al.
Reduction of insulin secretion in the insulinoma cell line INS-1 by overexpression of a Ca(v)2.3 (alpha1E) calcium channel antisense cassette.
Eur J Endocrinol. 2002; 146(6):881-9 [PubMed] Related Publications
OBJECTIVE: Multiple types of voltage-activated Ca(2+) channels (T, L, N, P, Q and R type) coordinate a variety of Ca(2+)-dependent processes in neurons and neuroendocrine cells. In insulinoma cell lines as well as in endocrine tissues, the non-L-type alpha1E (Ca(v)2.3) subunit is expressed as the tissue-specific splice variant alpha1Ee.
DESIGN AND METHODS: To understand the functional role of alpha1E-containing Ca(2+) channels, antisense alpha1E mRNA was overexpressed in INS-1 cells by stable transfection of an antisense alpha1E cassette cDNA. As controls, either a sense alpha1E cassette or a control vector containing enhanced green fluorescent protein as an unrelated gene was stably transfected. The overexpression of each transfected cassette cDNA was recorded by RT-PCR.
RESULTS: In three independent antisense alpha1E INS-1 clones, the glucose-induced insulin release was significantly reduced as compared with wild-type INS-1 cells and with a sense alpha1E INS-1 clone. However, in the antisense INS-1 clones, the KCl-induced insulin release was less impaired by overexpressing the antisense alpha1E cassette than the glucose-induced insulin release, leading to the assumption that glucose (15 mmol/l) and KCl (25 mmol/l) finally depolarize the membrane potential to a different extent.
CONCLUSION: alpha1E is involved in glucose-induced insulin secretion probably by influencing the excitability of INS-1 cells.

Vajna R, Klöckner U, Pereverzev A, et al.
Functional coupling between 'R-type' Ca2+ channels and insulin secretion in the insulinoma cell line INS-1.
Eur J Biochem. 2001; 268(4):1066-75 [PubMed] Related Publications
Among voltage-gated Ca2+ channels the non-dihydropyridine-sensitive alpha1E subunit is functionally less well characterized than the structurally related alpha1A (omega-agatoxin-IVA sensitive, P- /Q-type) and alpha1B (omega-conotoxin-GVIA sensitive, N-type) subunits. In the rat insulinoma cell line, INS-1, a tissue-specific splice variant of alpha1E (alpha1Ee) has been characterized at the mRNA and protein levels, suggesting that INS-1 cells are a suitable model for investigating the function of alpha1Ee. In alpha1E-transfected human embryonic kidney (HEK-293) cells the alpha1E-selective peptide antagonist SNX-482 (100 nM) reduces alpha1Ed- and alpha1Ee-induced Ba2+ inward currents in the absence and presence of the auxiliary subunits beta3 and alpha2delta-2 by more than 80%. The inhibition is fast and only partially reversible. No effect of SNX-482 was detected on the recombinant T-type Ca2+ channel subunits alpha1G, alpha1H, and alpha1I showing that the toxin from the venom of Hysterocrates gigas is useful as an alpha1E-selective antagonist. After blocking known components of Ca2+ channel inward current in INS-1 cells by 2 microM (+/-)-isradipine plus 0.5 microM omega-conotoxin-MVIIC, the remaining current is reduced by 100 nM SNX-482 from -12.4 +/- 1.2 pA/pF to -7.6 +/- 0.5 pA/pF (n = 9). Furthermore, in INS-1 cells, glucose- and KCl-induced insulin release are reduced by SNX-482 in a dose-dependent manner leading to the conclusion that alpha1E, in addition to L-type and non-L-type (alpha1A-mediated) Ca2+ currents, is involved in Ca2+ dependent insulin secretion of INS-1 cells.

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Cite this page: Cotterill SJ. CACNA1E, Cancer Genetics Web: http://www.cancer-genetics.org/CACNA1E.htm Accessed:

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