Functional Expression of T-Type Ca2+ Channels in Spinal Motoneurons of the Adult Turtle

Canto-Bustos, Martha; Loeza‐Alcocer, Emanuel; González‐Ramírez, Ricardo; Gandini, María A.; Delgado‐Lezama, Rodolfo; Felix, Ricardo

doi:10.1371/journal.pone.0108187

Cited by 14 publications

(12 citation statements)

References 41 publications

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“…Second, although the functional expression of Ca v 3.2 in mammalian motor neurons remains elusive, several studies suggest that T-type channels may have a functional role. For instance, Ca v 3.1 channels are present in turtle spinal motor neurons where they contribute to cellular excitability [34]. In addition, a low-threshold voltage-activated calcium conductance was reported at nodes of Ranvier in mouse spinal motor neurons, suggesting the presence of T-type channels [35].…”

Section: Discussionmentioning

confidence: 99%

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACN A1H encoding for Ca v 3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Ca v 3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominantnegative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Ca v 3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Ca v 3.2 channel function. These findings add to the notion that loss-of-function of Ca v 3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

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Section: Discussionmentioning

confidence: 99%

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

et al. 2020

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“…Therefore, our observation that the p.V681L and p.D1233H mutations caused a reduction of the window current could have an important consequence at early stages of muscle differentiation and may represent an underlying mechanism of infantile-onset amyotrophy ( Figure 5(a)). Additionally, several studies have reported the expression of T-type channels in motor neurons [31,32]. Although the role of T-type channels in motor neurons has not been investigated yet, it is likely that they contribute to some forms of neuronal excitability.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy

et al. 2019

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Neuromuscular disorders encompass a wide range of conditions often associated with a genetic component. In the present study, we report a patient with severe infantile-onset amyotrophy in whom two compound heterozygous variants in the gene CACNA1H encoding for Ca v 3.2 T-type calcium channels were identified. Functional analysis of Ca v 3.2 variants revealed several alterations of the gating properties of the channel that were in general consistent with a loss-of-channel function. Taken together, these findings suggest that severe congenital amyoplasia may be related to CACNA1H and would represent a new phenotype associated with mutations in this gene.

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“…Although recent studies have reported the expression of T-type channels in motor neurons,119 120 the functional implication of T-type channels in these neurons has yet to be analysed. Increased neuronal excitability has been reported as a hallmark in ALS, where an increase of the sodium conductance and a decrease of axonal potassium currents is observed 121.…”

Section: Cacna1h (Cav32) Channelopathiesmentioning

confidence: 99%

Genetic T-type calcium channelopathies

Weiss

Zamponi

2019

J Med Genet

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T-type channels are low-voltage-activated calcium channels that contribute to a variety of cellular and physiological functions, including neuronal excitability, hormone and neurotransmitter release as well as developmental aspects. Several human conditions including epilepsy, autism spectrum disorders, schizophrenia, motor neuron disorders and aldosteronism have been traced to variations in genes encoding T-type channels. In this short review, we present the genetics of T-type channels with an emphasis on structure-function relationships and associated channelopathies.

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Functional Expression of T-Type Ca2+ Channels in Spinal Motoneurons of the Adult Turtle

Cited by 14 publications

References 41 publications

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy

Genetic T-type calcium channelopathies

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