ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
The I-II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2+ channels: a paradigm for childhood absence epilepsy mutations.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 112 citations in OpenAlex.
- T-Type Voltage-Gated Calcium Channels: Potential Regulators of Smooth Muscle Contractility.International journal of molecular sciences · 2024Review
- Structural basis for human CaCell research · 2024Article
- The T-type calcium channelosome.Pflugers Archiv : European journal of physiology · 2024Review
- Electrophysiological characterization of a CaPflugers Archiv : European journal of physiology · 2023Article
- Genetic mechanisms in generalized epilepsies.Acta epileptologica · 2023Review
- Current Principles in the Management of Drug-Resistant Epilepsy.CNS drugs · 2022Article
- Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.Molecules (Basel, Switzerland) · 2022Review
- Contribution ofFrontiers in psychiatry · 2022Article
- Review
- Neuronal Cav3 channelopathies: recent progress and perspectives.Pflugers Archiv : European journal of physiology · 2020Review
- Cdk5-Dependent Phosphorylation of CaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy.Channels (Austin, Tex.) · 2019Article
- Pathogenic Cav3.2 channel mutation in a child with primary generalized epilepsy.Molecular brain · 2019Article
- A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- Contribution of S4 segments and S4-S5 linkers to the low-voltage activation properties of T-type CaV3.3 channels.PloS one · 2018Article
- Calmodulin regulates CaThe Journal of biological chemistry · 2017Article
- Functional variants inEpilepsia open · 2017Article
- Trafficking of neuronal calcium channels.Neuronal signaling · 2017Review
- A CaChannels (Austin, Tex.) · 2016Article
- Growth differentiation factor-15 promotes glutamate release in medial prefrontal cortex of mice through upregulation of T-type calcium channels.Scientific reports · 2016Article
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
Calcium currents via low-voltage-activated T-type channels mediate burst firing, particularly in thalamic neurons. Considerable evidence supports the hypothesis that overactive T-channels may contribute to thalamocortical dysrhythmia, including absence epilepsy. Single nucleotide polymorphisms in one of the T-channel genes (CACNA1H, which encodes Ca(v)3.2) are associated with childhood absence epilepsy in a Chinese population. Because only a fraction of these polymorphisms are predicted to increase channel activity and neuronal firing, we hypothesized that other channel properties may be affected. Here we describe that all the polymorphisms clustered in the intracellular loop connecting repeats I and II (I-II loop) increase the surface expression of extracellularly tagged Ca(v)3.2 channels. The functional domains within the I-II loop were then mapped by deletion analysis. The first 62 amino acids of the loop (post IS6) are involved in regulating the voltage dependence of channel gating and inactivation. Similarly, the last 15 amino acids of the loop (pre IIS1) are involved in channel inactivation. In contrast, the central region of I-II loop regulates surface expression, with no significant effect on channel biophysics. Electrophysiology, luminometry, fluorescence-activated cell sorting measurements, and confocal microscopy studies demonstrate that deletion of this central region leads to enhanced surface expression of channels from intracellular compartments to the plasma membrane. These results provide novel insights into how CACNA1H polymorphisms may contribute to Ca(v)3.2 channel overactivity and consequently to absence epilepsy and establish the I-II loop as an important regulator of Ca(v)3.2 channel function and expression.
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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.