ArticleThe Journal of biological chemistry2008
Characterization of the gating brake in the I-II loop of Ca(v)3.2 T-type Ca(2+) channels.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy.Annals of neurology · 2017Trial
- Theoretical Study of the Structural Stability, Chemical Reactivity, and Protein Interaction for NMP Compounds as Modulators of the Endocannabinoid System.Molecules (Basel, Switzerland) · 2022Article
- Contribution ofFrontiers in psychiatry · 2022Article
- Cdk5-Dependent Phosphorylation of CaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Genetic T-type calcium channelopathies.Journal of medical genetics · 2020Review
- Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy.Channels (Austin, Tex.) · 2019Article
- Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2.Frontiers in physiology · 2019Article
- 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
- Evolutionary insights into T-type CaThe Journal of general physiology · 2017Article
- Contrasting the roles of the I-II loop gating brake in CaV3.1 and CaV3.3 calcium channels.Pflugers Archiv : European journal of physiology · 2015Article
- Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Inhibition of Cav3.2 T-type Calcium Channels by Its Intracellular I-II Loop.The Journal of biological chemistry · 2015Article
- Cav3 T-type channels: regulators for gating, membrane expression, and cation selectivity.Pflugers Archiv : European journal of physiology · 2014Review
- Ins and outs of T-channel structure function.Pflugers Archiv : European journal of physiology · 2014Review
- Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility.The Journal of physiology · 2014Article
- Cooperative activation of the T-type CaV3.2 channel: interaction between Domains II and III.The Journal of biological chemistry · 2013Article
- Neurochemical and behavioral features in genetic absence epilepsy and in acutely induced absence seizures.ISRN neurology · 2013Article
- The role of a voltage-dependent Ca2+ channel intracellular linker: a structure-function analysis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2012Article
- Article
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Authors and funding
10 authors.
Funding
Abstract
Mutations in the I-II loop of Ca(v)3.2 channels were discovered in patients with childhood absence epilepsy. All of these mutations increased the surface expression of the channel, whereas some mutations, and in particular C456S, altered the biophysical properties of channels. Deletions around C456S were found to produce channels that opened at even more negative potentials than control, suggesting the presence of a gating brake that normally prevents channel opening. The goal of the present study was to identify the minimal sequence of this brake and to provide insights into its structure. A peptide fragment of the I-II loop was purified from bacteria, and its structure was analyzed by circular dichroism. These results indicated that the peptide had a high alpha-helical content, as predicted from secondary structure algorithms. Based on homology modeling, we hypothesized that the proximal region of the I-II loop may form a helix-loop-helix structure. This model was tested by mutagenesis followed by electrophysiological measurement of channel gating. Mutations that disrupted the helices, or the loop region, had profound effects on channel gating, shifting both steady state activation and inactivation curves, as well as accelerating channel kinetics. Mutations designed to preserve the helical structure had more modest effects. Taken together, these studies showed that any mutations in the brake, including C456S, disrupted the structural integrity of the brake and its function to maintain these low voltage-activated channels closed at resting membrane potentials.
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