Inherited Neuronal Ion Channelopathies: New Windows on Complex Neurological Diseases

Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium chann...

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Bibliographic Details
Published in:The Journal of neuroscience 2008-11, Vol.28 (46), p.11768-11777
Main Authors: Catterall, William A, Dib-Hajj, Sulayman, Meisler, Miriam H, Pietrobon, Daniela
Format: Article
Language:English
Subjects:
Animals
Brain - metabolism
Brain - physiopathology
Brain Diseases - genetics
Brain Diseases - metabolism
Brain Diseases - physiopathology
Calcium Channels - genetics
Calcium Channels - metabolism
Channelopathies - genetics
Channelopathies - metabolism
Channelopathies - physiopathology
Disease Models, Animal
Genetic Predisposition to Disease - genetics
Humans
Ion Channels - genetics
Ion Channels - metabolism
Mutation - genetics
Neurons - metabolism
Symposia and Mini-Symposia
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Summary:Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium channel Na(V)1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. Mutations in the peripheral sodium channel Na(V)1.7 cause familial pain syndromes. Gain-of-function mutations cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain because of attenuation of action potential firing. These experiments have defined correlations between genotype and phenotype in chronic pain diseases and focused attention on Na(V)1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca(V)2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. These mutations increase activation at negative membrane potentials and increase evoked neurotransmitter release at cortical glutamatergic synapses. Studies of a mouse genetic model show that these gain-of-function effects lead to cortical spreading depression, aura, and potentially migraine. Overall, these experiments indicate that imbalance in the activity of excitatory and inhibitory neurons is an important underlying cause of these diseases.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/JNEUROSCI.3901-08.2008