Divergent sodium channel defects in familial hemiplegic migraine

Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37240, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2008; 105(28):9799-804. DOI: 10.1073/pnas.0711717105
Source: PubMed


Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na(V)1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human beta(1) and beta(2) accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na(V)1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na(V)1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.

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    • "SLC1A3 (encoding the glial glutamate transporter EAAT1) and SLC4A4 (encoding the electrogenic sodium bicarbonate cotransporter NBCe1) have been proposed as potential fourth and fifth genes (FHM4 and FHM5) responsible for pure hemiplegic migraine [52, 56]. Functional studies of mutations at each FHM locus in animal and model cells have shown that various missense mutations, large and small scale deletions exist and greatly affect the conductive properties of the channels upsetting the balance of ions in neurons [57]. The flow of ions is critical for normal physiological functioning and any disruption can make people more susceptible to developing these severe headaches. "
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    ABSTRACT: Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people's daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies.
    Current Genomics 08/2013; 14(5):300-315. DOI:10.2174/13892029113149990007 · 2.34 Impact Factor
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    • "Thus far, genotype–phenotype relationships of Na V 1.1 FHM mutations are more elusive. As for epileptogenic mutations, both loss and gain of function effects have been reported in heterologous systems (Cestele et al., 2008; Kahlig et al., 2008), but animal models have not been generated yet. However, studies of mutations in the predominant brain splicing variant indicated a gain of function of FHM mutations (Cestele et al., 2008). "
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    ABSTRACT: Purpose: To report the identification of the T1174S SCN1A (NaV 1.1) mutation in a three-generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the pathomechanism. Methods: The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA-201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K). Key findings: The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (I(NaP)), consistent with gain of function. The I(NaP) increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions. Significance: Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype-phenotype relationship of SCN1A mutations.
    Epilepsia 02/2013; 54(5). DOI:10.1111/epi.12123 · 4.57 Impact Factor
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    • ", A and B). For example, the time to peak activation for Na V 1.9 (9.4 ms at 30 mV; Fig. 2 B) is several fold slower than the TTX-sensitive Na V 1.1 (1.1 ms at 30 mV; Kahlig et al., 2008). Inactivation of Na V 1.9 is also slow and highly voltage sensitive (Fig. 2 C). "
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    ABSTRACT: Tetrodotoxin (TTX)-resistant voltage-gated Na (Na(V)) channels have been implicated in nociception. In particular, Na(V)1.9 contributes to expression of persistent Na current in small diameter, nociceptive sensory neurons in dorsal root ganglia and is required for inflammatory pain sensation. Using ND7/23 cells stably expressing human Na(V)1.9, we elucidated the biophysical mechanisms responsible for potentiation of channel activity by G-protein signaling to better understand the response to inflammatory mediators. Heterologous Na(V)1.9 expression evoked TTX-resistant Na current with peak activation at -40 mV with extensive overlap in voltage dependence of activation and inactivation. Inactivation kinetics were slow and incomplete, giving rise to large persistent Na currents. Single-channel recording demonstrated long openings and correspondingly high open probability (P(o)) accounting for the large persistent current amplitude. Channels exposed to intracellular GTPγS, a proxy for G-protein signaling, exhibited twofold greater current density, slowing of inactivation, and a depolarizing shift in voltage dependence of inactivation but no change in activation voltage dependence. At the single-channel level, intracellular GTPγS had no effect on single-channel amplitude but caused an increased mean open time and greater P(o) compared with recordings made in the absence of GTPγS. We conclude that G-protein activation potentiates human Na(V)1.9 activity by increasing channel open probability and mean open time, causing the larger peak and persistent current, respectively. Our results advance our understanding about the mechanism of Na(V)1.9 potentiation by G-protein signaling during inflammation and provide a cellular platform useful for the discovery of Na(V)1.9 modulators with potential utility in treating inflammatory pain.
    The Journal of General Physiology 02/2013; 141(2):193-202. DOI:10.1085/jgp.201210919 · 4.79 Impact Factor
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