 |
||||
|
||||
|
||||
|
||||
|
||||
The Journal of Neuroscience, November 12, 2008, 28(46):11768-11777; doi:10.1523/JNEUROSCI.3901-08.2008
Previous Article | Next Article
Symposia and Mini-Symposia
Inherited Neuronal Ion Channelopathies: New Windows on Complex Neurological Diseases
William A. Catterall,1 Sulayman Dib-Hajj,2,3 Miriam H. Meisler,4 andDaniela Pietrobon5 1Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, 2Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, 3Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, 4Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-5618, and 5Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, 35121 Padova, Italy
Correspondence should be addressed to William A. Catterall, Department of Pharmacology, University of Washington, Seattle, WA 98195. Email: wcatt{at}u.washington.edu
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.
Key words: sodium channels; calcium channels; epilepsy; migraine; pain; genetic diseases
Received Aug. 15, 2008; revised Sept. 18, 2008; accepted Oct. 10, 2008.
Correspondence should be addressed to William A. Catterall, Department of Pharmacology, University of Washington, Seattle, WA 98195. Email: wcatt{at}u.washington.edu
This article has been cited by other articles:
K. Drasner
Spinal anaesthesia: a century of refinement, and failure is still an option
Br. J. Anaesth., June 1, 2009; 102(6): 729 - 730.
[Full Text] [PDF]
|
|
|
|
 |
|