Lower Affinity of Isradipine for L-Type Ca<sup>2+</sup> Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease

Ortner, Nadine J.; Bock, Gabriella; Dougalis, Antonios; Kharitonova, Maria; Duda, Johanna; Heß, Simon; Tuluc, Petronel; Pomberger, Thomas; Stefanova, Nadia; Pitterl, Florian; Ciossek, Thomas; Oberacher, Herbert; Draheim, Henning J.; Kloppenburg, Peter; Liss, Birgit; Striessnig, Jörg

doi:10.1523/jneurosci.2946-16.2017

Cited by 76 publications

(127 citation statements)

References 87 publications

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“…tsA-201 cells were maintained in culture and transiently transfected with wild-type (WT) or mutant Ca v 1.3 α 1 - and auxiliary β 3 - (NM_012828) and α 2 δ-1- (NM_001082276) subunits as previously described [9,26]. GFP was co-transfected to visualize transfected cells.…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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

et al. 2018

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“…A recent study has challenged this conclusion (Ortner et al, 2017). The authors claim that systemic administration of isradipine does not protect SNc DA neurons against striatal injection of 6-OHDA.…”

Section: The Rationale For a Cav1 Ca2+ Channel Inhibitormentioning

confidence: 99%

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

Surmeier

Halliday

Simuni

2017

Experimental Neurology

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Parkinson’s disease is characterized by progressively distributed Lewy pathology and neurodegeneration. The motor symptoms of cPD are unequivocally linked to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several features of these neurons appear to make them selectively vulnerable to factors thought to cause cPD, like aging, genetic mutations and environmental toxins. Among these features, Ca2+ entry through Cav1 channels is particularly amenable to pharmacotherapy in early stage cPD patients. This review outlines the linkage between these channels, mitochondrial oxidant stress and cPD pathogenesis. It also summarizes considerations that went into the design and execution of the ongoing Phase 3 clinical trial with an inhibitor of these channels – isradipine.

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“…Although there is indirect evidence to support this proposition (3), there is no direct demonstration that this is the case. A third caveat, which has recently been argued (32), is that even if Ca 2+ entry through Cav1 channels triggers mitochondrial damage in vivo, it is not evident that a sufficient level of channel inhibition can be achieved with systemic drug administration to diminish it.…”

Section: Introductionmentioning

confidence: 99%

Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress

Guzmán

Ilijić

Yang

et al. 2018

Journal of Clinical Investigation

116

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The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass - demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.

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Lower Affinity of Isradipine for L-Type Ca²⁺ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease

Cited by 76 publications

References 87 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

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress

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Lower Affinity of Isradipine for L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease

Cited by 76 publications

References 87 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

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress

Contact Info

Product

Resources

About

Lower Affinity of Isradipine for L-Type Ca²⁺ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease

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