ArticleThe Journal of biological chemistry2008
Modulation of voltage- and Ca2+-dependent gating of CaV1.3 L-type calcium channels by alternative splicing of a C-terminal regulatory domain.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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Who cites it
99 citing papers in PubMed, 168 citations in OpenAlex.
- Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation.The Journal of general physiology · 2026Article
- C-Terminus of CaCells · 2026Article
- Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944.The Journal of general physiology · 2026Article
- Nanoscale architecture and dynamics of CaJournal of molecular and cellular cardiology plus · 2025Article
- Exploring the potential for gene therapy in Cav1.4-related retinal channelopathies.Channels (Austin, Tex.) · 2025Review
- Article
- Role of Cav1.3 Channels in Brain-Heart Interactions: An Unexpected Journey.Biomedicines · 2025Review
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- CaBP1 and 2 enable sustained CaeLife · 2024Article
- Role of the CaChannels (Austin, Tex.) · 2024Article
- Opto-chemogenetic inhibition of L-type CaCell reports methods · 2024Article
- Presynaptic Proteins and Their Roles in Visual Processing by the Retina.Annual review of vision science · 2024Review
- Pathogenicity of de novo CACNA1D CaEuropean journal of human genetics : EJHG · 2024Article
- Selective blockade of CaNature communications · 2024Article
- Clustering of CaJournal of neurochemistry · 2023Article
- Regulation of Cardiac Cav1.2 Channels by Calmodulin.International journal of molecular sciences · 2023Review
- CACNA1D-Related Channelopathies: From Hypertension to Autism.Handbook of experimental pharmacology · 2023Review
- Pathophysiology of CaFrontiers in physiology · 2023Review
- RNA epitranscriptomics dysregulation: A major determinant for significantly increased risk of ASD pathogenesis.Frontiers in neuroscience · 2023Article
- Calcium Channels in Retinal Function and Disease.Annual review of vision science · 2022Review
39 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Low voltage activation of Ca(V)1.3 L-type Ca(2+) channels controls excitability in sensory cells and central neurons as well as sinoatrial node pacemaking. Ca(V)1.3-mediated pacemaking determines neuronal vulnerability of dopaminergic striatal neurons affected in Parkinson disease. We have previously found that in Ca(V)1.4 L-type Ca(2+) channels, activation, voltage, and calcium-dependent inactivation are controlled by an intrinsic distal C-terminal modulator. Because alternative splicing in the Ca(V)1.3 alpha1 subunit C terminus gives rise to a long (Ca(V)1.3(42)) and a short form (Ca(V)1.3(42A)), we investigated if a C-terminal modulatory mechanism also controls Ca(V)1.3 gating. The biophysical properties of both splice variants were compared after heterologous expression together with beta3 and alpha2delta1 subunits in HEK-293 cells. Activation of calcium current through Ca(V)1.3(42A) channels was more pronounced at negative voltages, and inactivation was faster because of enhanced calcium-dependent inactivation. By investigating several Ca(V)1.3 channel truncations, we restricted the modulator activity to the last 116 amino acids of the C terminus. The resulting Ca(V)1.3(DeltaC116) channels showed gating properties similar to Ca(V)1.3(42A) that were reverted by co-expression of the corresponding C-terminal peptide C(116). Fluorescence resonance energy transfer experiments confirmed an intramolecular protein interaction in the C terminus of Ca(V)1.3 channels that also modulates calmodulin binding. These experiments revealed a novel mechanism of channel modulation enabling cells to tightly control Ca(V)1.3 channel activity by alternative splicing. The absence of the C-terminal modulator in short splice forms facilitates Ca(V)1.3 channel activation at lower voltages expected to favor Ca(V)1.3 activity at threshold voltages as required for modulation of neuronal firing behavior and sinoatrial node pacemaking.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.