The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of Ca V 1.2 L-type calcium channels
Open accessAbstract
Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca 2+ channels. After membrane depolarization, Ca 2+ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca 2+ 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 Ca 2+ 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 β 1 subunits prominent in brain, as well as β 2 subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca 2+ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly 406 . As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at ≈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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This mutation leads to decreased calcium- and voltage-dependent inactivation of the channel.
“This mutation leads to decreased calcium- and voltage-dependent inactivation of the channel1,9.”
From Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome (2011) · cites this paper as [9]
In mice, this missense mutation leads to increased Ca2+ currents and loss of voltage-dependent channel inactivation.
“Studies in mice indicate that this missense mutation leads to increased Ca2+ currents and loss of voltage-dependent channel inactivation31,77.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [77]
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- Authors
- Barrett, C. F., & Tsien, R. W.
- Affiliations
- Stanford Medicine (US)
- ORCID
- Tsien, Richard W.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-02-12
- Volume
- 105
- Issue
- 6
- Pages
- 2157-2162
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2538892
- OpenAlex
- W2152717615
- Cited by
- 174
- References
- 56
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 13 · 2017: 11 · 2016: 11 · 2015: 10 · 2014: 12 · 2013: 14 · 2012: 13
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32HL007708)
- National Institute of General Medical Sciences (R01GM058234)
- National Institute of Neurological Disorders and Stroke (R01NS024067)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- Timothy syndrome, Cav1.2 L-type calcium channel, voltage-dependent inactivation, calcium-dependent inactivation, channel gating, beta1 subunit, beta2 subunit, autism spectrum disorder, cardiac arrhythmias
- MeSH terms
- Autistic Disorder, Cell Line, Humans, Mutation, Syndrome, Ion Channel Gating, Mutagenesis, Site-Directed, Calcium Channels, L-Type
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