ArticleThe Journal of physiology2003
Five ADNFLE mutations reduce the Ca2+ dependence of the mammalian alpha4beta2 acetylcholine response.
Article in The Journal of physiology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 85 citations in OpenAlex.
- Emerging Role of Tripartite Synaptic Transmission in the Pathomechanism of Autosomal-Dominant Sleep-Related Hypermotor Epilepsy.International journal of molecular sciences · 2025Review
- Subcortical Circuits Among Pedunculopontine Nucleus, Thalamus and Basal Ganglia Play Important Roles in Paroxysmal Arousal in Genetic Rat Models of Autosomal Dominant Sleep-Related Hypermotor Epilepsy.International journal of molecular sciences · 2025Article
- Age-Dependent Activation of Purinergic Transmission Contributes to the Development of Epileptogenesis in ADSHE Model Rats.Biomolecules · 2024Article
- Stoichiometry-selective modulation of α4β2 nicotinic ACh receptors by divalent cations.British journal of pharmacology · 2022Article
- Can rodent models elucidate the pathomechanisms of genetic epilepsy?British journal of pharmacology · 2022Review
- Age-Dependent and Sleep/Seizure-Induced Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy.International journal of molecular sciences · 2020Article
- Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Pathogenesis and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant α4 subunit of nicotinic ACh receptor.British journal of pharmacology · 2020Article
- Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant α4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Distinctive effects of nicotinic receptor intracellular-loop mutations associated with nocturnal frontal lobe epilepsy.Neuropharmacology · 2016Article
- Article
- The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy.Frontiers in physiology · 2015Review
- Channelopathies.Korean journal of pediatrics · 2014Review
- Mice expressing the ADNFLE valine 287 leucine mutation of the Β2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function.Pharmacology, biochemistry, and behavior · 2013Article
- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy.Nature genetics · 2012Article
- Neuronal nicotinic receptors in sleep-related epilepsy: studies in integrative biology.ISRN biochemistry · 2012Review
- Recent advances in gene manipulation and nicotinic acetylcholine receptor biology.Biochemical pharmacology · 2011Review
- Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2009Article
- Genetic basis in epilepsies caused by malformations of cortical development and in those with structurally normal brain.Human genetics · 2009Review
- Nicotine normalizes intracellular subunit stoichiometry of nicotinic receptors carrying mutations linked to autosomal dominant nocturnal frontal lobe epilepsy.Molecular pharmacology · 2009Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Five nicotinic acetylcholine receptor (nAChR) mutations are currently linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The similarity of their clinical symptoms suggests that a common functional anomaly of the mutations underlies ADNFLE seizures. To identify this anomaly, we constructed rat orthologues (S252F, +L264, S256L, V262L, V262M) of the human ADNFLE mutations, expressed them in Xenopus oocytes with the appropriate wild-type (WT) subunit (alpha4 or beta2), and studied the Ca2+ dependence of their ACh responses. All the mutations significantly reduced 2 mM Ca2+-induced increases in the 30 microM ACh response (P < 0.05). Consistent with a dominant mode of inheritance, this reduction persisted in oocytes injected with a 1:1 mixture of mutant and WT cRNA. BAPTA injections showed that the reduction was not due to a decrease in the secondary activation of Ca2+-activated Cl- currents. The S256L mutation also abolished 2 mM Ba2+ potentiation of the ACh response. The S256L, V262L and V262M mutations had complex effects on the ACh concentration-response relationship but all three mutations shifted the concentration-response relationship to the left at [ACh] >= 30 microM. Co-expression of the V262M mutation with a mutation (E180Q) that abolished Ca2+ potentiation resulted in 2 mM Ca2+ block, rather than potentiation, of the 30 microM ACh response, suggesting that the ADNFLE mutations reduce Ca2+ potentiation by enhancing Ca2+ block of the alpha4beta2 nAChR. Ca2+ modulation may prevent presynaptic alpha4beta2 nAChRs from overstimulating glutamate release at central excitatory synapses during bouts of synchronous, repetitive activity. Reducing the Ca2+ dependence of the ACh response could trigger seizures by increasing alpha4beta2-mediated glutamate release during such bouts.
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