ArticleThe Journal of biological chemistry2011
Regulation of the mutually exclusive exons 8a and 8 in the CaV1.2 calcium channel transcript by polypyrimidine tract-binding protein.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 77 citations in OpenAlex.
- Trial
- Congenital Long QT Syndrome: From Conventional Management to Emerging Biological Therapies.Reviews in cardiovascular medicine · 2026Review
- Dysregulated RNA-binding proteins and alternative splicing: Emerging roles in autism spectrum disorder.Molecules and cells · 2025Review
- The emerging role of anoctamin-1 in cardiac and cerebrovascular diseases.Frontiers in cardiovascular medicine · 2025Review
- Article
- Article
- Calcium and activity-dependent signaling in the developing cerebral cortex.Development (Cambridge, England) · 2022Review
- A matter of space and time: Emerging roles of disease-associated proteins in neural development.Neuron · 2022Review
- Biological impact of mutually exclusive exon switching.PLoS computational biology · 2021Article
- Voltage-Gated Calcium Channels in Nonexcitable Tissues.Annual review of physiology · 2021Review
- Identification and Characterization of a Minimal Functional Splicing Regulatory Protein, PTBP1.Biochemistry · 2020Article
- A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development.FEBS open bio · 2020Article
- Review
- Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.eLife · 2019Article
- RBM20 Regulates CaV1.2 Surface Expression by Promoting Exon 9* Inclusion ofInternational journal of molecular sciences · 2019Article
- A developmentally regulated spliced variant of PTBP1 is upregulated in type 1 diabetic hearts.Biochemical and biophysical research communications · 2019Article
- RNA processing in skeletal muscle biology and disease.Transcription · 2019Review
- Post-Translational Modifications in Polypyrimidine Tract Binding Proteins PTBP1 and PTBP2.Biochemistry · 2018Article
- Genome‑wide analysis and prediction of functional long noncoding RNAs in osteoblast differentiation under simulated microgravity.Molecular medicine reports · 2017Article
- The determinants of alternative RNA splicing in human cells.Molecular genetics and genomics : MGG · 2017Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
CaV1.2 calcium channels play roles in diverse cellular processes such as gene regulation, muscle contraction, and membrane excitation and are diversified in their activity through extensive alternative splicing of the CaV1.2 mRNA. The mutually exclusive exons 8a and 8 encode alternate forms of transmembrane segment 6 (IS6) in channel domain 1. The human genetic disorder Timothy syndrome is caused by mutations in either of these two CaV1.2 exons, resulting in disrupted Ca(2+) homeostasis and severe pleiotropic disease phenotypes. The tissue-specific pattern of exon 8/8a splicing leads to differences in symptoms between patients with exon 8 or 8a mutations. Elucidating the mechanisms controlling the exon 8/8a splicing choice will be important in understanding the spectrum of defects associated with the disease. We found that the polypyrimidine tract-binding protein (PTB) mediates a switch from exon 8 to 8a splicing. PTB and its neuronal homolog, nPTB, are widely studied splicing regulators controlling large sets of alternative exons. During neuronal development, PTB expression is down-regulated with a concurrent increase in nPTB expression. Exon 8a is largely repressed in embryonic mouse brain but is progressively induced during neuronal differentiation as PTB is depleted. This splicing repression is mediated by the direct binding of PTB to sequence elements upstream of exon 8a. The nPTB protein is a weaker repressor of exon 8a, resulting in a shift in exon choice when nPTB replaces PTB in cells. These results provide mechanistic understanding of how these two exons, important for human disease, are controlled.
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