Correction: Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila.
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ABSTRACT:
SUBMITTER: PLOS Genetics Staff
PROVIDER: S-EPMC4749325 | biostudies-other | 2016 Feb
REPOSITORIES: biostudies-other
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Project description:Bang sensitive (BS) Drosophila mutants display characteristic seizure-like phenotypes resembling, in some aspects, those of human seizure disorders such as epilepsy. The BS mutant parabss1, caused by a gain-of-function mutation of the voltage-gated Na+ channel gene, is extremely seizure-sensitive with phenotypes that have proven difficult to ameliorate by anti-epileptic drug feeding or by seizure-suppressor mutation. It has been presented as a model for intractable human epilepsy. Here we show that cacophony (cacTS2), a mutation of the Drosophila presynaptic Ca++ channel ?1 subunit gene, is a particularly potent seizure-suppressor mutation, reverting seizure-like phenotypes for parabss1 and other BS mutants. Seizure-like phenotypes for parabss1 may be suppressed by as much as 90% in double mutant combinations with cacTS2. Unexpectedly, we find that parabss1 also reciprocally suppresses cacTS2 seizure-like phenotypes. The cacTS2 mutant displays these seizure-like behaviors and spontaneous high-frequency action potential firing transiently after exposure to high temperature. We find that this seizure-like behavior in cacTS2 is ameliorated by 85% in double mutant combinations with parabss1.
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Project description:Voltage-gated calcium channels play a key role in chemical synaptic transmission by providing the calcium trigger for regulated neurotransmitter release. Genes encoding the primary structural subunit, alpha1, as well as accessory subunits of presynaptic calcium channels have now been identified in a variety of organisms. The cacophony (cac) gene in Drosophila, also known as nightblind A, encodes a voltage-gated calcium-channel alpha1 subunit homologous to vertebrate alpha1 subunits implicated in neurotransmitter release. A recent genetic screen in our laboratory isolated cac(TS2), a conditional cac mutant exhibiting rapid paralysis at elevated temperatures. This mutant has allowed synaptic electrophysiology after acute perturbation of a specific calcium-channel gene product, demonstrating that cac encodes a primary calcium channel functioning in neurotransmitter release. Here we report the molecular lesion in cac(TS2), a missense mutation within a calcium-dependent regulatory domain of the alpha1 subunit, as well as phenotypic rescue of temperature-sensitive and lethal cac mutations by transgenic expression of a wild-type cac cDNA. Notably, rescue of rapid, calcium-triggered neurotransmitter release was achieved by neural expression of a single cDNA containing a subset of alternative exons and lacking any conserved synaptic-protein interaction sequence. Possible implications of these findings are discussed in the context of structure-function studies of synaptic calcium channels, as well as alternative splicing and mRNA editing of the cac transcript.
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Project description:We have cloned cDNAs that encode a complete open reading frame for a calcium channel alpha1 subunit from Drosophila melanogaster. The deduced 1851 amino acid protein belongs to the superfamily of voltage-gated sodium and calcium channels. Phylogenetic analysis shows that the sequence of this subunit is relatively distant from sodium channel alpha subunits and most similar to genes encoding the A, B, and E isoforms of calcium channel alpha1 subunits. To indicate its similarity to this subfamily of vertebrate isoforms, we name this protein Dmca1A, for Drosophila melanogaster calcium channel alpha1 subunit, type A. Northern blot analysis detected a single 10. 5 kb transcript class that is regulated developmentally, with expression peaks in the first larval instar, midpupal, and late pupal stages. In late-stage embryos, Dmca1A is expressed preferentially in the nervous system. Variant transcripts are generated by alternative splicing. In addition, single nucleotide variations between cDNAs and genomic sequence are consistent with RNA editing. Dmca1A maps to a chromosomal region implicated in, and is the likely candidate for, the gene involved in the generation of behavioral, physiological, and lethal phenotypes of the cacophony, nightblind-A, and lethal(1)L13 mutants.
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Project description:Timothy syndrome (TS) is a very rare multisystem disorder almost exclusively associated with mutations G402S and G406R in helix IS6 of Cav1.2. Recently, mutations R518C/H in helix IIS0 of the voltage sensing domain II (VSD-II) were described as a cause of cardiac-only TS. The three mutations are known to decelerate voltage-dependent inactivation (VDI). Here, we report a case of cardiac-only TS caused by mutation R518C. To explore possible impact of the three mutations on interdomain contacts, we modeled channel Cav1.2 using as templates Class Ia and Class II cryo-EM structures of presumably inactivated channel Cav1.1. In both models, R518 and several other residues in VSD-II donated H-bonds to the IS6-linked α1-interaction domain (AID). We further employed steered Monte Carlo energy minimizations to move helices S4-S5, S5, and S6 from the inactivated-state positions to those seen in the X-ray structures of the open and closed NavAb channel. In the open-state models, positions of AID and VSD-II were similar to those in Cav1.1. In the closed-state models, AID moved along the β subunit (Cavβ) toward the pore axis and shifted AID-bound VSD-II. In all the models R518 retained strong contacts with AID. Our calculations suggest that conformational changes in VSD-II upon its deactivation would shift AID along Cavβ toward the pore axis. The AID-linked IS6 would bend at flexible G402 and G406, facilitating the activation gate closure. Mutations R518C/H weakened the IIS0-AID contacts and would retard the AID shift. Mutations G406R and G402S stabilized the open state and would resist the pore closure. Several Cav1.2 mutations associated with long QT syndromes are consistent with this proposition. Our results provide a mechanistic rationale for the VDI deceleration caused by TS-associated mutations and suggest targets for further studies of calcium channelopathies.
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Project description:Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.
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