The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi, Gerald W.; Striessnig, Jörg; Koschak, Alexandra; Dolphin, Annette C.

doi:10.1124/pr.114.009654

Cited by 872 publications

(1,042 citation statements)

References 747 publications

(844 reference statements)

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“…These include muscle contraction, gene transcription, hormone secretion, neurotransmitter release, synaptic excitability and plasticity [1–3]. Their subcellular targeting as well as the dynamics of Ca 2+ entry need to be tightly controlled by accessory subunits, post-translational modification, lipid- and protein interactions, as well as alternative splicing [1,2]. The occurrence of human channelopathies resulting from even minor changes in Ca 2+ channel activity [4–8] further emphasizes the importance of strictly regulated channel gating and targeting for normal physiological function.…”

Section: Introductionmentioning

confidence: 99%

“…Due to the known physiological role of Ca v 1.3 for brain development and function [2,18] and the recent findings of recurrent de novo germline CACNA1D mutations in patients with neuropsychiatric and neurological symptoms this gene has been incorporated in custom genetic panels for clinical diagnosis, including autism/intellectual disability (Autism/ID Xpanded Panel).…”

Section: Introductionmentioning

confidence: 99%

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Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

et al. 2018

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Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the α1-subunit of voltage-gated Cav1.3 Ca2+-channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk.Here we report the functional characterization of previously identified CACNA1D APA mutations F747L and M1354I using whole-cell patch-clamp electrophysiology upon recombinant expression in tsA-201 cells. We also investigated if alternative splicing of Cav1.3 affects the aberrant gating of the previously characterized APA mutation R990H and two mutations associated with autism spectrum disorder (A479G and G407R). Splice-variant dependent gating changes are of particular interest for germline mutations, since the relative expression of Cav1.3 splice variants differs across different tissues and within brain regions and might therefore result in tissue-specific phenotypes. Our data revealed a complex gain-of-function phenotype for APA mutation F747L confirming its pathogenic role. Furthermore, we found splice-variant dependent gating changes in R990H, A749G and G407R. M1354I did not change channel function of Cav1.3 splice variants and should therefore be considered a rare non-pathogenic variant until further proof for its pathogenicity is obtained. Our new findings together with previously published data allow classification of pathogenic CACNA1D mutations into four categories based on prototypical functional changes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

et al. 2018

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“…Because of negative activation threshold below −60 mV these channels can contribute to the initial phase of cell depolarization at the foot of an action potential. Ca V 3 channels participate in physiological functions such as generation of low threshold spikes leading to neuronal burst firing, neuronal communication via neurotransmitter and hormone release and cell proliferation [3]. In spite of extensive research, structural determinants of negative activation threshold remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Role of individual S4 segments in gating of Ca_v3.1 T-type calcium channel by voltage

et al. 2018

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Contributions of voltage sensing S4 segments in domains I – IV of CaV3.1 channel to channel activation were analyzed. Neutralization of the uppermost charge in individual S4 segments by exchange of arginine for cysteine was employed. Mutant channels with single exchange in domains I – IV, in two adjacent domains, and in all four domains were constructed and expressed in HEK 293 cells. Changes in maximal gating charge Qmax and the relation between Qmax and maximal conductance Gmax were evaluated. Qmax was the most affected by single mutation in domain I and by double mutations in domains I + II and I + IV. The ratio Gmax/Qmax proportional to opening probability of the channel was significantly decreased by the mutation in domain III and increased by mutations in domains I and II. In channels containing double mutations Gmax/Qmax ratio increased significantly when the mutation in domain I was included. Mutations in domains II and III zeroed each other. Mutation in domain IV prevented the decrease caused by the mutation in domain III. Neither ion current nor gating current was observed when channels with quadruple mutations were expressed. Immunocytochemistry analysis did not reveal the presence of channel protein in the cell membrane. Likely, quadruple mutation results in a structural change that affects the channel’s trafficking mechanism. Altogether, S4 segments in domains I-IV of the CaV3.1 channel unequally contribute to channel gating by voltage. We suggest the most important role of the voltage sensor in the domain I and lesser roles of voltage sensors in domains II and III.

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“…The α1-subunit, which contains four homologous but nonidentical repeats, dictates the major biophysical and pharmacological properties of Ca v s, but the auxiliary subunits play key roles in regulating channel gating and trafficking [1,3,4].…”

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confidence: 99%

“…It will surely spur structural elucidation of other Ca v s and investigation of the structural basis of Ca v drug actions. Among these drugs, dihydropyridines (e.g., amlodipine), phenylalkylamines (e.g., verapamil) and benzothiazepines (e.g., diltiazem) are used to treat hypertension, angina pectoris and cardiac arrhythmias and target the α1-subunit of Ca v 1.2, whereas gabapentin and pregabalin are used to treat epilepsy and neuropathic pain and target the α2δ-subunit of Ca v s in the nervous system [1,4]. The binding sites of dihydropyridines and phenylalkylamines have been identified recently in Ca v Ab [10], but whether these drugs bind in the same way in Ca v 1.2 remains to be determined.…”

mentioning

confidence: 99%

Calcium channel structures come of age

Yang

2016

Cell Res

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The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Cited by 872 publications

References 747 publications

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Role of individual S4 segments in gating of Ca_v3.1 T-type calcium channel by voltage

Calcium channel structures come of age

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The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Cited by 872 publications

References 747 publications

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

Role of individual S4 segments in gating of Cav3.1 T-type calcium channel by voltage

Calcium channel structures come of age

Contact Info

Product

Resources

About

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Role of individual S4 segments in gating of Ca_v3.1 T-type calcium channel by voltage