CACNA1C-Related Channelopathies

Herold, Kevin; Hussey, John W.; Dick, Ivy E.

doi:10.1007/164_2022_624

Cited by 10 publications

(20 citation statements)

References 142 publications

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“…Similar to the previous reports (Boczek et al, 2015;Bozarth et al, 2018;Rodan et al, 2021;Herold et al, 2023), our patients presented with West syndrome, ID, ADHD, and cardiac arrhythmias. Although our mutants displayed decreased calcium current densities and reduced mRNA and protein expressions, we found that our variants could induce cell apoptosis, and affect mitochondrial functions by interfering with mitochondrial complexes, mitochondrial calcium ions influx, ATP production, ROS production, mitochondrial fusion, and fission as well as mitophagy process.…”

Section: Discussionsupporting

confidence: 91%

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

Kessi

Chen

Pan

et al. 2023

Front. Mol. Neurosci.

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ObjectiveTo investigate the pathogenesis of three novel de novo CACNA1C variants (p.E411D, p.V622G, and p.A272V) in causing neurodevelopmental disorders and arrhythmia.MethodsSeveral molecular experiments were carried out on transfected human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells to explore the effects of p.E411D, p.V622G, and p.A272V variants on electrophysiology, mitochondrial and lysosomal functions. Electrophysiological studies, RT-qPCR, western blot, apoptosis assay, mito-tracker fluorescence intensity, lyso-tracker fluorescence intensity, mitochondrial calcium concentration test, and cell viability assay were performed. Besides, reactive oxygen species (ROS) levels, ATP levels, mitochondrial copy numbers, mitochondrial complex I, II, and cytochrome c functions were measured.ResultsThe p.E411D variant was found in a patient with attention deficit-hyperactive disorder (ADHD), and moderate intellectual disability (ID). This mutant demonstrated reduced calcium current density, mRNA, and protein expression, and it was localized in the nucleus, cytoplasm, lysosome, and mitochondria. It exhibited an accelerated apoptosis rate, impaired autophagy, and mitophagy. It also demonstrated compromised mitochondrial cytochrome c oxidase, complex I, and II enzymes, abnormal mitochondrial copy numbers, low ATP levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, and elevated mitochondrial calcium ions. The p.V622G variant was identified in a patient who presented with West syndrome and moderate global developmental delay. The p.A272V variant was found in a patient who presented with epilepsy and mild ID. Both mutants (p.V622G and p.A272V) exhibited reduced calcium current densities, decreased mRNA and protein expressions, and they were localized in the nucleus, cytoplasm, lysosome, and mitochondria. They exhibited accelerated apoptosis and proliferation rates, impaired autophagy, and mitophagy. They also exhibited abnormal mitochondrial cytochrome c oxidase, complex I and II enzymes, abnormal mitochondrial copy numbers, low ATP, high ROS levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, as well as elevated mitochondrial calcium ions.ConclusionThe p.E411D, p.V622G and p.A272V mutations of human CACNA1C reduce the expression level of CACNA1C proteins, and impair mitochondrial and lysosomal functions. These effects induced by CACNA1C variants may contribute to the pathogenesis of CACNA1C-related disorders.

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Section: Discussionsupporting

confidence: 91%

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

Kessi

Chen

Pan

et al. 2023

Front. Mol. Neurosci.

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“…Beyond this, CaV1.2 and/or CaV1.3 channels play important roles in various physiological settings including: (1) tuning insulin secretion in pancreatic beta cells 12 , (2) regulating AP firing and catecholamine release from adrenal chromaffin cells 13 , (3) smooth muscle contraction tuned Ca 2+ -entry through CaV1.2 14 , (3) vesicle secretion from ribbon synapses in inner ear hair cells that relies exclusively on presynaptic CaV1.3 15 , and (4) varied emerging functions in non-excitable cells 16 . Alterations in CaV1.2 and CaV1.3 are, therefore, linked to diverse clinical phenotypes (see reviews [17][18][19] ). Heterozygous gain-of-function CaV1.2 variants are linked to Timothy Syndrome, a multisystem disorder characterized by prolonged QT interval, syndactyly, and autism spectrum disorders (ASD) 20 .…”

Section: Introductionmentioning

confidence: 99%

A Genetically Encoded Actuator Selectively Boosts L-type Calcium Channels in Diverse Physiological Settings

del Rivero Morfin,

Chavez,

Jayaraman

et al. 2023

Preprint

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L-type Ca2+ channels (CaV1.2/1.3) convey influx of calcium ions (Ca2+) that orchestrate a bevy of biological responses including muscle contraction and gene transcription. Deficits in CaV1 function play a vital role in cardiac and neurodevelopmental disorders. Yet conventional pharmacological approaches to upregulate CaV1 are limited, as excessive Ca2+ influx leads to cytotoxicity. Here, we develop a genetically encoded enhancer of CaV1.2/1.3 channels (GeeC) to manipulate Ca2+ entry in distinct physiological settings. Specifically, we functionalized a nanobody that targets the CaV macromolecular complex by attaching a minimal effector domain from a CaV enhancer-leucine rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeC evoked a 3-fold increase in L-type current amplitude. In neurons, GeeC augmented excitation-transcription (E-T) coupling. In all, GeeC represents a powerful strategy to boost CaV1.2/1.3 function in distinct physiological settings and, in so doing, lays the groundwork to illuminate new insights on neuronal and cardiac physiology and disease.

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“…Alterations in CACNA1C are consistently associated with an increased risk of schizophrenia, as well as other neuropsychiatric disorders typified by prefrontal cortex dysfunction . Variants in CACNA1C are numerous, and their impact on channel function is complex and a topic of current research . Current data suggest that the impact of a variant may depend on where the channel is expressed, with distinct molecular interactions in a tissue-specific manner .…”

Section: Discussionmentioning

confidence: 70%

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

Datta,

Yang,

Joyce

et al. 2024

JAMA Psychiatry

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ImportanceThe risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.ObjectiveTo examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.Design, Setting, and ParticipantsThe design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.Main Outcomes and MeasuresOutcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.ResultsLayer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.Conclusions and RelevanceThe layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

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CACNA1C-Related Channelopathies

Cited by 10 publications

References 142 publications

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

A Genetically Encoded Actuator Selectively Boosts L-type Calcium Channels in Diverse Physiological Settings

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

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