Inherited neuronal ion channelopathies: new windows on complex neurological diseases

WA Catterall, S Dib-Hajj, MH Meisler… - Journal of …, 2008 - Soc Neuroscience
WA Catterall, S Dib-Hajj, MH Meisler, D Pietrobon
Journal of Neuroscience, 2008Soc Neuroscience
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 …
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 NaV1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in NaV1.1 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 NaV1.7 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 NaV1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, CaV2.1, 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.
Soc Neuroscience