ArticleProceedings of the National Academy of Sciences of the United States of America2006
Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- Calcium and arrhythmogenesis.Physiological reviews · 2007Pooled it
- A Seven Amino Acid Long Region in the Cardiac CaCells · 2026Article
- Regulation of Cardiac Cav1.2 Channels by Calmodulin.International journal of molecular sciences · 2023Review
- Inactivation influences the extent of inhibition of voltage-gated CaFrontiers in physiology · 2023Article
- The CaNeuropharmacology · 2022Article
- CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms.The Journal of general physiology · 2022Article
- Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome.Pflugers Archiv : European journal of physiology · 2020Review
- Article
- Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside.Experimental biology and medicine (Maywood, N.J.) · 2019Article
- Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2-neo mouse rescued by L-type calcium channel blockers.The Journal of physiology · 2019Article
- Calmodulinopathy: Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes.Frontiers in cardiovascular medicine · 2018Review
- Identification of a novel cAMP dependent protein kinase A phosphorylation site on the human cardiac calcium channel.Scientific reports · 2017Article
- Methods, Tools and Current Perspectives in Proteogenomics.Molecular & cellular proteomics : MCP · 2017Review
- Impact of SNPs on Protein Phosphorylation Status in Rice (Oryza sativa L.).International journal of molecular sciences · 2016Article
- hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism.Oncotarget · 2016Article
- Calcium Revisited: New Insights Into the Molecular Basis of Long-QT Syndrome.Circulation. Arrhythmia and electrophysiology · 2016Review
- Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression.Science (New York, N.Y.) · 2016Article
- Differential CaMKII regulation by voltage-gated calcium channels in the striatum.Molecular and cellular neurosciences · 2015Article
- A phosphorylation-related variant ADD1-rs4963 modifies the risk of colorectal cancer.PloS one · 2015Article
- A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain.Molecular psychiatry · 2014Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Calcium channels in the plasma membrane rarely remain open for much more than a millisecond at any one time, which avoids raising intracellular calcium to toxic levels. However, the dihydropyridine-sensitive calcium channels of the CaV1 family, which selectively couple electrical excitation to endocrine secretion, cardiovascular contractility, and neuronal transcription, have a unique second mode of gating, "mode 2," that involves frequent openings of much longer duration. Here we report that two human conditions, cyclosporin neurotoxicity and Timothy syndrome, increase mode 2 gating of the recombinant rabbit CaV1.2 channel. In each case, mode 2 gating depends on a Ser residue at the cytoplasmic end of the S6 helix in domain I (Ser-439, Timothy syndrome) or domain IV (Ser-1517, cyclosporin). Both Ser reside in consensus sequences for type II calmodulin-dependent protein kinase. Pharmacologically inhibiting type II calmodulin-dependent protein kinase or mutating the Ser residues to Ala prevents the increase in mode 2 gating. We propose that aberrant phosphorylation, or "phosphorylopathy," of the CaV1.2 channel protein contributes to the excitotoxicity associated with Timothy syndrome and with chronic cyclosporin treatment of transplant patients.
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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.