Ca2+ Channel Blockers

Striessnig, Jörg; Ortner, Nadine J.

doi:10.1007/978-3-030-21573-6_34-1

Cited by 2 publications

(1 citation statement)

References 16 publications

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“…The second question is if Cav1.3 channels in the brain are efficiently blocked at therapeutic doses of DHPs. The therapeutic target of DHPs for cardiovascular indications is Cav1.2 L-type channels in arterial smooth muscle cells [78,85]. It is known that under identical experimental conditions Cav1.2 channels are about 5 times more sensitive to inhibition by DHPs than Cav1.3 [62,94].…”

Section: Clinical Characteristics Of Germline Cacna1d Variantsmentioning

confidence: 99%

De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism

Ortner

Kaserer

Copeland

et al. 2020

Pflugers Arch - Eur J Physiol

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The identification of rare disease-causing variants in humans by large-scale next-generation sequencing (NGS) studies has also provided us with new insights into the pathophysiological role of de novo missense variants in the CACNA1D gene that encodes the pore-forming α1-subunit of voltage-gated Cav1.3 L-type Ca 2+ channels. These CACNA1D variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca 2+ influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic CACNA1D variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca 2+ channel blockers as a potential therapeutic option. Keywords Voltage-gated Ca 2+ channels. CACNA1D. Neurodevelopmental disorders. Autism spectrum disorders. Calcium channel blockers. Variants

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Section: Clinical Characteristics Of Germline Cacna1d Variantsmentioning

confidence: 99%

De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism

Ortner

Kaserer

Copeland

et al. 2020

Pflugers Arch - Eur J Physiol

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Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

Striessnig

2021

Front. Synaptic Neurosci.

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This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.

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Ca2+ Channel Blockers

Cited by 2 publications

References 16 publications

De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism

De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism

Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

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