Nonfunctional Na_V1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Cestèle S.; Schiavon E.; Rusconi R.Franceschetti S.Mantegazza M.

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Nonfunctional Na_V1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

机译：Nonfunctional Na_V1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

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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 Na_v1.1 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 Na_V1.1 FHM mutations have generated controversial results. In particular, it has been shown that the Na_V1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to Na_V1.1 mutants that cause severe epilepsy, but we have observed gain-offunction effects for other Na_V1.1 FHM mutants. Here we show that Na_V1.1-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 Na_V1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of Na_V1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第43期|17546-17551|共6页
作者
Cestèle S.; Schiavon E.; Rusconi R.Franceschetti S.Mantegazza M.;
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作者单位

Laboratoire D'Excellence Canaux Ioniques D'Intérêt Thérapeutique, Institute of Molecular and Cellular Pharmacology, University of Nice Sophia Antipolis, 06560 Valbonne, France;

Department of Neurophysiopathology, Carlo Besta Foundation Neurological Institute, 20133 Milan, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Ankyrin; Calmodulin; Dravet syndrome; Generalized epilepsy with febrile seizures plus; Spreading depression;

Nonfunctional Na_V1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

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