ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 91 citations in OpenAlex.
- Hemiplegic migraine: genetics and pathophysiology.The Journal of clinical investigation · 2026Review
- Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.Cell death & disease · 2024Article
- A combination of chlorzoxazone and folic acid improves recognition memory, anxiety and depression in SCA3-84Q mice.Human molecular genetics · 2024Article
- Oxytocin Receptor in Cerebellar Purkinje Cells Does Not Engage in Autism-Related Behaviors.Cerebellum (London, England) · 2023Article
- A chlorzoxazone-folic acid combination improves cognitive affective decline in SCA2-58Q mice.Scientific reports · 2023Article
- Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia.Life (Basel, Switzerland) · 2023Review
- A neurodevelopmental disorder caused by a dysfunctionaleNeurologicalSci · 2023Article
- Clinical and genetic characterization of CACNA1A-related disease.Clinical genetics · 2022Article
- Electrophysiological Studies Support Utility of Positive Modulators of SK Channels for the Treatment of Spinocerebellar Ataxia Type 2.Cerebellum (London, England) · 2022Review
- Complex effects on CaScientific reports · 2022Article
- Mechanism of stress-induced attacks in an episodic neurologic disorder.Science advances · 2022Article
- Subtype-selective positive modulation of KBritish journal of pharmacology · 2022Article
- Fampridine and Acetazolamide in EA2 and Related Familial EA: A Prospective Randomized Placebo-Controlled Trial.Neurology. Clinical practice · 2021Article
- A Chlorzoxazone-Baclofen Combination Improves Cerebellar Impairment in Spinocerebellar Ataxia Type 1.Movement disorders : official journal of the Movement Disorder Society · 2021Article
- The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function.Molecular brain · 2021Article
- Hydrophobic interactions between the HA helix and S4-S5 linker modulate apparent CaActa physiologica (Oxford, England) · 2021Article
- In vivo analysis of the spontaneous firing of cerebellar Purkinje cells in awake transgenic mice that model spinocerebellar ataxia type 2.Cell calcium · 2021Article
- Rare CACNA1A mutations leading to congenital ataxia.Pflugers Archiv : European journal of physiology · 2020Review
- Article
- Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6.Brain communications · 2020Article
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α(1A)-subunit of Ca(V)2.1 channels and thereby either decrease or increase neuronal Ca(2+) influx. A decreased Ca(V)2.1-mediated Ca(2+) influx has been shown to reduce the regularity of cerebellar Purkinje cell activity and to induce episodic cerebellar ataxia. However, little is known about how ataxia can be caused by CACNA1A mutations that increase the Ca(2+) influx, such as the S218L missense mutation. Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence of Ca(V)2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic action potentials and dendritic Ca(2+) spikes and in disrupted firing patterns. The hyperexcitability of Cacna1a(S218L) Purkinje cells was counteracted by application of the activators of Ca(2+)-dependent K(+) channels, 1-EBIO and chlorzoxazone (CHZ). Moreover, 1-EBIO also alleviated the irregularity of Purkinje cell firing both in vitro and in vivo, while CHZ improved the irregularity of Purkinje cell firing in vitro as well as the motor performance of Cacna1a(S218L) mutant mice. The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar ataxia induced by the S218L mutation and they advocate a general therapeutic approach in that targeting Ca(2+)-dependent K(+) channels may be beneficial for treating ataxia not only in patients suffering from a decreased Ca(2+) influx, but also in those suffering from an increased Ca(2+) influx in their Purkinje cells.
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