ArticleThe Journal of biological chemistry2011
Timothy mutation disrupts the link between activation and inactivation in Ca(V)1.2 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 22 papers.
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Who cites it
22 citing papers in PubMed.
- A Novel De Novo Gain-of-FunctionNeurology. Genetics · 2024Article
- Central Causation of Autism/ASDs via Excessive [CaBrain sciences · 2024Review
- Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.Expert reviews in molecular medicine · 2023Review
- The effect of alterations of schizophrenia-associated genes on gamma band oscillations.Schizophrenia (Heidelberg, Germany) · 2022Article
- Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside.Experimental biology and medicine (Maywood, N.J.) · 2019Article
- Alterations in Schizophrenia-Associated Genes Can Lead to Increased Power in Delta Oscillations.Cerebral cortex (New York, N.Y. : 1991) · 2019Article
- Computational Modeling of Genetic Contributions to Excitability and Neural Coding in Layer V Pyramidal Cells: Applications to Schizophrenia Pathology.Frontiers in computational neuroscience · 2019Article
- Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2.Frontiers in physiology · 2019Article
- Calcium channel gating.Pflugers Archiv : European journal of physiology · 2018Review
- Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia.Channels (Austin, Tex.) · 2018Review
- Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling.Translational psychiatry · 2017Article
- Key role of segment IS4 in Cav1.2 inactivation: link between activation and inactivation.Pflugers Archiv : European journal of physiology · 2017Article
- Upward movement of IS4 and IIIS4 is a rate-limiting stage in CaPflugers Archiv : European journal of physiology · 2016Article
- Molecular Dynamics Simulations of KirBac1.1 Mutants Reveal Global Gating Changes of Kir Channels.Journal of chemical information and modeling · 2015Article
- Functional characterization of CaVα2δ mutations associated with sudden cardiac death.The Journal of biological chemistry · 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
- Methods for quantification of pore-voltage sensor interaction in Ca(V)1.2.Pflugers Archiv : European journal of physiology · 2014Article
- Channelopathy pathogenesis in autism spectrum disorders.Frontiers in genetics · 2013Review
- Genome-wide Membrane Protein Structure Prediction.Current genomics · 2013Article
- Neutralisation of a single voltage sensor affects gating determinants in all four pore-forming S6 segments of Ca(V)1.2: a cooperative gating model.Pflugers Archiv : European journal of physiology · 2012Article
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6 authors.
Funding
Abstract
The Timothy syndrome mutations G402S and G406R abolish inactivation of Ca(V)1.2 and cause multiorgan dysfunction and lethal arrhythmias. To gain insights into the consequences of the G402S mutation on structure and function of the channel, we systematically mutated the corresponding Gly-432 of the rabbit channel and applied homology modeling. All mutations of Gly-432 (G432A/M/N/V/W) diminished channel inactivation. Homology modeling revealed that Gly-432 forms part of a highly conserved structure motif (G/A/G/A) of small residues in homologous positions of all four domains (Gly-432 (IS6), Ala-780 (IIS6), Gly-1193 (IIIS6), Ala-1503 (IVS6)). Corresponding mutations in domains II, III, and IV induced, in contrast, parallel shifts of activation and inactivation curves indicating a preserved coupling between both processes. Disruption between coupling of activation and inactivation was specific for mutations of Gly-432 in domain I. Mutations of Gly-432 removed inactivation irrespective of the changes in activation. In all four domains residues G/A/G/A are in close contact with larger bulky amino acids from neighboring S6 helices. These interactions apparently provide adhesion points, thereby tightly sealing the activation gate of Ca(V)1.2 in the closed state. Such a structural hypothesis is supported by changes in activation gating induced by mutations of the G/A/G/A residues. The structural implications for Ca(V)1.2 activation and inactivation gating are discussed.
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