ArticleProceedings of the National Academy of Sciences of the United States of America2008
The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers, 1 of them a synthesis that pooled it.
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Who cites it
112 citing papers in PubMed, 1 synthesis or guideline pooled it, 175 citations in OpenAlex.
- Geno- and phenotypic characteristics and clinical outcomes ofFrontiers in cardiovascular medicine · 2022Pooled it
- Aberrant calcium signaling and neuronal activity in the L271H CACNA1D (Cav1.3) iPSC model of neurodevelopmental disease.Molecular psychiatry · 2026Article
- Structure of a polymorphic repeat at theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structure of a polymorphic repeat at themedRxiv : the preprint server for health sciences · 2025Article
- Article
- Disruptions in primary visual cortex physiology and function in a mouse model of Timothy syndrome.Cerebral cortex (New York, N.Y. : 1991) · 2025Article
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- Central Causation of Autism/ASDs via Excessive [CaBrain sciences · 2024Review
- Calcium- and calmodulin-dependent inhibition of NMDA receptor currents.Biophysical journal · 2024Review
- Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels.The Journal of general physiology · 2024Article
- Regulation of Cardiac Cav1.2 Channels by Calmodulin.International journal of molecular sciences · 2023Review
- CACNA1C-Related Channelopathies.Handbook of experimental pharmacology · 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
- High value-added application of a renewable bioresource as acaricide: Investigation the mechanism of action of scoparone againstJournal of advanced research · 2022Article
- Enhanced long-term potentiation and impaired learning in mice lacking alternative exon 33 of CaTranslational psychiatry · 2022Article
- Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome.PloS one · 2022Article
- Brain-on-a-Chip: Dream or Reality?Frontiers in neuroscience · 2022Article
- Involvement of Calcium-Dependent Pathway and β Subunit-Interaction in Neuronal Migration and Callosal Projection Deficits Caused by the Cav1.2 I1166T Mutation in Developing Mouse Neocortex.Frontiers in neuroscience · 2021Article
52 more citing papers are in PubMed but not listed here.
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2 authors at 1 institution in 1 country.
Funding
Abstract
Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca2+ channels. After membrane depolarization, Ca2+ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca2+ channel activity is perturbed in a rare yet devastating disorder known as Timothy syndrome (TS), whose features include autism or autism spectrum disorder along with severe cardiac arrhythmia and developmental abnormalities. Most cases of TS arise from a sporadic single nucleotide change that generates a mutation (G406R) in the pore-forming subunit of the L-type Ca2+ channel Ca(V)1.2. We found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI. The deceleration of VDI was observed when the L-type channels were expressed with beta1 subunits prominent in brain, as well as beta2 subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca2+ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly406. As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. Thus, the TS mutation offers a unique perspective on mechanisms of inactivation as well as a promising starting point for exploring the underlying pathophysiology of autism.
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