Journal Article

Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Franceschetti, Silvana, Cestèle, Sandrine, Mantegazza, Massimo, Schiavon, Emanuele, Rusconi, Raffaella

2013

Overview

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-of-function 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.

• Publisher: National Academy of Sciences,NATIONAL ACADEMY OF SCIENCES,National Acad Sciences
• Subject: Algorithms / Amino Acid Substitution / Animals / Ankyrins / Behavioral neuroscience / Biological and medical sciences / Biological Sciences / Cell Line / Cells / Cells, Cultured / Computational modeling / Computer Simulation / Current density / Electric potential / Epilepsy / Fundamental and applied biological sciences. Psychology / GABAergic Neurons - metabolism / GABAergic Neurons - physiology / genes / Genetic mutation / Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy / human cell lines / Humans / Ion Channel Gating - genetics / Ion Channel Gating - physiology / Life Sciences / Low temperature / Medical sciences / Membrane Potentials - genetics / Membrane Potentials - physiology / Mice / Mice, Inbred C57BL / Migraine / Migraine with Aura - genetics / Migraine with Aura - pathology / Migraine with Aura - physiopathology / Mutants / Mutation / NAV1.1 Voltage-Gated Sodium Channel - chemistry / NAV1.1 Voltage-Gated Sodium Channel - genetics / NAV1.1 Voltage-Gated Sodium Channel - physiology / Nervous system (semeiology, syndromes) / Neurology / Neurons / Neurons - metabolism / Neurons - physiology / Patch-Clamp Techniques / plasma membrane / Proteins / sodium / Sodium channels / temperature / Vertebrates: nervous system and sense organs