Nonfunctional Na V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects
| Autor: | Raffaella Rusconi, Emanuele Schiavon, Silvana Franceschetti, Massimo Mantegazza, Sandrine Cestèle |
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| Rok vydání: | 2013 |
| Předmět: |
Patch-Clamp Techniques
Migraine with Aura Mutant Biology medicine.disease_cause Cell Line Membrane Potentials Mice medicine Animals Humans Ankyrin Computer Simulation GABAergic Neurons Cells Cultured Familial hemiplegic migraine Loss function Neurons Genetics chemistry.chemical_classification Mutation Multidisciplinary Biological Sciences medicine.disease Mice Inbred C57BL NAV1.1 Voltage-Gated Sodium Channel Amino Acid Substitution chemistry Cortical spreading depression NAV1 Ion Channel Gating Generalized epilepsy with febrile seizures plus Algorithms |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:17546-17551 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Mutations causing FHM type 3 have been identified in SCN1A, the gene encoding the Nav1.1 Na(+) channel, which is also a major target of epileptogenic mutations and is particularly important for the excitability of GABAergic neurons. However, functional studies of NaV1.1 FHM mutations have generated controversial results. In particular, it has been shown that the NaV1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to NaV1.1 mutants that cause severe epilepsy, but we have observed gain-of-function effects for other NaV1.1 FHM mutants. Here we show that NaV1.1-L1649Q is nonfunctional because of folding defects that are rescuable by incubation at lower temperatures or coexpression of interacting proteins, and that a partial rescue is sufficient for inducing an overall gain of function because of the modifications in gating properties. Strikingly, when expressed in neurons, the mutant was partially rescued and was a constitutive gain of function. A computational model showed that 35% rescue can be sufficient for inducing gain of function. Interestingly, previously described folding-defective epileptogenic NaV1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of NaV1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3. |
| Databáze: | OpenAIRE |
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