Novel &lt;i&gt;SCN3B&lt;/i&gt; Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5

Ishikawa, Taisuke; Takahashi, Naohiko; Ohno, Seiko; Sakurada, Harumizu; Nakamura, Kazufumi; On, Young Keun; Park, Jeong Euy; Makiyama, Takeru; Horie, Minoru; Arimura, Takuro; Makita, Naomasa; Kimura, Akinori

doi:10.1253/circj.cj-12-0995

Cited by 72 publications

(49 citation statements)

References 36 publications

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“…For example, mutations in the predominant cardiac sodium channel gene SCN5A are associated with LQTS, Brugada syndrome, and VF (Remme and Bezzina 2010). Mutations in VGSC β subunits SCN1B, SCN2B, and SCN3B are linked to Brugada syndrome, which confers increased risk of sudden cardiac death due to VF (Watanabe et al 2008;Riuro et al 2013;Ishikawa et al 2013). Mutations in SCN1B, SCN2B, SCN3B, and SCN4B are linked to AF (Watanabe et al 2009;Olesen et al 2011;Li et al 2013).…”

Section: Cardiac Arrhythmiamentioning

confidence: 99%

The Role of Non-pore-Forming β Subunits in Physiology and Pathophysiology of Voltage-Gated Sodium Channels

Isom

2014

Handbook of Experimental Pharmacology

111

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Voltage-gated sodium channel β1 and β2 subunits were discovered as auxiliary proteins that co-purify with pore-forming α subunits in brain. The other family members, β1B, β3, and β4, were identified by homology and shown to modulate sodium current in heterologous systems. Work over the past 2 decades, however, has provided strong evidence that these proteins are not simply ancillary ion channel subunits, but are multifunctional signaling proteins in their own right, playing both conducting (channel modulatory) and nonconducting roles in cell signaling. Here, we discuss evidence that sodium channel β subunits not only regulate sodium channel function and localization but also modulate voltage-gated potassium channels. In their nonconducting roles, VGSC β subunits function as immunoglobulin superfamily cell adhesion molecules that modulate brain development by influencing cell proliferation and migration, axon outgrowth, axonal fasciculation, and neuronal pathfinding. Mutations in genes encoding β subunits are linked to paroxysmal diseases including epilepsy, cardiac arrhythmia, and sudden infant death syndrome. Finally, β subunits may be targets for the future development of novel therapeutics.

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Section: Cardiac Arrhythmiamentioning

confidence: 99%

The Role of Non-pore-Forming β Subunits in Physiology and Pathophysiology of Voltage-Gated Sodium Channels

Isom

2014

Handbook of Experimental Pharmacology

111

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“…5A). The V110I mutation in β3 has been linked to Brugada syndrome and also affects a residue buried within a hydrophobic core, resulting in reduced channel expression (47). Interestingly, the first epileptogenic mutation attributed to Nav channel β-subunits is a Cys-to-Trp substitution that disrupts the disulfide bridge within the extracellular domain of β1 (30).…”

Section: Mutating 58mentioning

confidence: 99%

Crystallographic insights into sodium-channel modulation by the β4 subunit

Gilchrist

Das

Petegem

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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Voltage-gated sodium (Na v ) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, β-subunits modify Na v channel function and cause debilitating disorders when mutated. While investigating whether β-subunits also influence ligand interactions, we found that β4 dramatically alters toxin binding to Na v 1.2. To explore these observations further, we solved the crystal structure of the extracellular β4 domain and identified 58 Cys as an exposed residue that, when mutated, eliminates the influence of β4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of β4. Disrupting this bridge by introducing a β1 mutation implicated in epilepsy repositions the 58 Cys-containing loop and disrupts β4 modulation of Na v 1.2. Overall, the principles emerging from this work (i) help explain tissuedependent variations in Na v channel pharmacology; (ii) enable the mechanistic interpretation of β-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant β-subunit behavior.voltage-gated sodium channel | beta4 subunit | ProTx-II | X-ray structure | disease mutations

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“…Another trafficking mutation, b3 p.V110I, was similarly found in 3 Japanese patients with BrS from a cohort of 181 individuals. 71 Because of the high prevalence of b3 p.V110I in SCN5A mutation-negative Japanese patients with BrS (10.5% familial cases and 0.6% sporadic cases), a recommendation was made to begin testing for SCN3B mutations in the SCN5A-negative Japanese BrS patients. 72 b3 trafficking mutation, p.V54G, was identified in IVF 50 and SIDS.…”

Section: Ventricular Arrhythmiamentioning

confidence: 99%