Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels

Kawai, Takafumi; Hashimoto, Masaki; Eguchi, Natsuki; Nishino, Junko M.; Jinno, Yuka; Mori-Kreiner, Risa; Aspåker, Måns; Chiba, Daisuke; Ohtsuka, Yukio; Kawanabe, Akira; Nishino, Atsuo; Okamura, Yasushi

doi:10.1016/j.jbc.2021.100783

Cited by 4 publications

(1 citation statement)

References 67 publications

(119 reference statements)

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“…Interestingly, some invertebrates express more primitive Na V 1 channels containing the DEKA selectivity filter that nevertheless appear to have some calcium permeability ( 58 ). This suggests that additional aspects of Na V 1 evolution, including changes to other residues lining the pore may confer additional ion selectivity/permeability properties ( 59 ). Consistent with this, recurrent SCN2A missense variants that affect pore-adjacent arginine residues R379 and R937 eliminate permeation altogether ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

Echevarria-Cooper

Hawkins

Misra

et al. 2022

Human Molecular Genetics

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Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms, and features of autism spectrum disorder. Prior structure–function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance, and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired action potential initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the action potential, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal EEG abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.

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Section: Discussionmentioning

confidence: 99%

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

Echevarria-Cooper

Hawkins

Misra

et al. 2022

Human Molecular Genetics

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Cellular and behavioral effects of altered Na_V1.2 sodium channel ion permeability in Scn2a^K1422E mice

Echevarria-Cooper

Hawkins²,

Misra

et al. 2021

Preprint

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Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to infantile epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to developmental delay and/or autism spectrum disorder with or without co-morbid seizures. One unique case less easily classified using this binary paradigm is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms, and features of autism spectrum disorder. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance, and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model that predicted mixed effects on channel function and neuronal activity. We also generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Dissociated neurons from heterozygous Scn2aK1422E/+ mice exhibited a novel TTX-resistant current with a reversal potential consistent with mixed ion permeation. Cortical slice recordings from Scn2aK1422E/+ tissue demonstrated impaired action potential initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the action potential, suggesting mixed effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal EEG abnormalities, altered response to induced seizures, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from Scn2a knockout models, consistent with mixed effects of K1422E on NaV1.2 channel function.

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The trunk–tail junctional region in Ciona larvae autonomously expresses tail-beating bursts at ∼20 second intervals

Hara

Hasegawa

Iwatani

et al. 2022

Journal of Experimental Biology

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Swimming locomotion in aquatic vertebrates, such as fish and tadpoles, is expressed through neuron networks in the spinal cord. These networks are arranged in parallel, ubiquitously distributed, and mutually coupled along the spinal cord to express undulation patterns accommodated to various inputs into the networks. While these systems have been widely studied in vertebrate swimmers, their evolutionary origin along the chordate phylogeny remains unclear. Ascidians, representing a sister group of vertebrates, give rise to tadpole larvae that swim freely in seawater. In the present study, we examined the locomotor ability of the anterior and posterior body fragments of larvae of the ascidian Ciona that had been cut at an arbitrary position. Examinations of more than 200 fragments revealed a necessary and sufficient body region that spanned only ∼10% of the body length and included the trunk-tail junction. “Mid-piece” body fragments, which included the trunk-tail junctional region, but excluded most of the anterior trunk and posterior tail, autonomously expressed periodic tail-beating bursts at ∼20-s intervals. We compared the durations and intervals of tail-beating bursts expressed by mid-piece fragments, and also by whole larvae under different sensory conditions. The results obtained suggested that body parts outside the mid-piece had effects to shorten swimming intervals, particularly in the dark, and to vary durations of bursts. We propose that Ciona larvae express swimming behaviors by modifying autonomous and periodic locomotor drives that operate locally in the trunk-tail junctional region.

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Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels

Cited by 4 publications

References 67 publications

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

Cellular and behavioral effects of altered Na_V1.2 sodium channel ion permeability in Scn2a^K1422E mice

The trunk–tail junctional region in Ciona larvae autonomously expresses tail-beating bursts at ∼20 second intervals

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Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels

Cited by 4 publications

References 67 publications

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice

The trunk–tail junctional region in Ciona larvae autonomously expresses tail-beating bursts at ∼20 second intervals

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Cellular and behavioral effects of altered Na_V1.2 sodium channel ion permeability in Scn2a^K1422E mice