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Proc Natl Acad Sci U S A
2013 Dec 17;11051:E5016-24. doi: 10.1073/pnas.1314557110.
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Crystallographic insights into sodium-channel modulation by the β4 subunit.
Gilchrist J
,
Das S
,
Van Petegem F
,
Bosmans F
.
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Voltage-gated sodium (Nav) 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 Nav 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 Nav1.2. 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 Nav1.2. Overall, the principles emerging from this work (i) help explain tissue-dependent variations in Nav 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.
Abriel,
Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins.
2005, Pubmed
Abriel,
Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins.
2005,
Pubmed
Aman,
Regulation of persistent Na current by interactions between beta subunits of voltage-gated Na channels.
2009,
Pubmed
Auld,
A rat brain Na+ channel alpha subunit with novel gating properties.
1988,
Pubmed
,
Xenbase
Bant,
Control of transient, resurgent, and persistent current by open-channel block by Na channel beta4 in cultured cerebellar granule neurons.
2010,
Pubmed
Baroni,
Functional modulation of voltage-dependent sodium channel expression by wild type and mutated C121W-β1 subunit.
2013,
Pubmed
Bosmans,
Deconstructing voltage sensor function and pharmacology in sodium channels.
2008,
Pubmed
,
Xenbase
Brackenbury,
Na Channel β Subunits: Overachievers of the Ion Channel Family.
2011,
Pubmed
Brackenbury,
Voltage-gated Na+ channels: potential for beta subunits as therapeutic targets.
2008,
Pubmed
Brünger,
Crystallography & NMR system: A new software suite for macromolecular structure determination.
1998,
Pubmed
Buffington,
Na+ channel-dependent recruitment of Navβ4 to axon initial segments and nodes of Ranvier.
2013,
Pubmed
Béress,
Isolation and characterisation of three polypeptides with neurotoxic activity from Anemonia sulcata.
1975,
Pubmed
Catterall,
International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.
2005,
Pubmed
Chanda,
Coupling interactions between voltage sensors of the sodium channel as revealed by site-specific measurements.
2004,
Pubmed
Chen,
Identification of the cysteine residue responsible for disulfide linkage of Na+ channel α and β2 subunits.
2012,
Pubmed
Chioni,
A novel adhesion molecule in human breast cancer cells: voltage-gated Na+ channel beta1 subunit.
2009,
Pubmed
Cusdin,
The sodium channel {beta}3-subunit induces multiphasic gating in NaV1.3 and affects fast inactivation via distinct intracellular regions.
2010,
Pubmed
Céard,
Purification of the main beta-toxin from Tityus serrulatus scorpion venom using high-performance liquid chromatography.
1992,
Pubmed
Dib-Hajj,
The Na(V)1.7 sodium channel: from molecule to man.
2013,
Pubmed
Diss,
Beta-subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression.
2008,
Pubmed
Egri,
A thermoprotective role of the sodium channel β1 subunit is lost with the β1 (C121W) mutation.
2012,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Farmer,
Splice variants of Na(V)1.7 sodium channels have distinct β subunit-dependent biophysical properties.
2012,
Pubmed
Fendri-Kriaa,
New mutation c.374C>T and a putative disease-associated haplotype within SCN1B gene in Tunisian families with febrile seizures.
2011,
Pubmed
Gee,
The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel.
1996,
Pubmed
George,
Inherited disorders of voltage-gated sodium channels.
2005,
Pubmed
Ho,
Differential expression of sodium channel β subunits in dorsal root ganglion sensory neurons.
2012,
Pubmed
Ishikawa,
Novel SCN3B mutation associated with brugada syndrome affects intracellular trafficking and function of Nav1.5.
2013,
Pubmed
Isom,
Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel.
1992,
Pubmed
,
Xenbase
Isom,
Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif.
1995,
Pubmed
,
Xenbase
Jover,
The correlation between Na+ channel subunits and scorpion toxin-binding sites. A study in rat brain synaptosomes and in brain neurons developing in vitro.
1988,
Pubmed
Kabsch,
XDS.
2010,
Pubmed
Karshikoff,
Ion pairs and the thermotolerance of proteins from hyperthermophiles: a "traffic rule" for hot roads.
2001,
Pubmed
Kazen-Gillespie,
Cloning, localization, and functional expression of sodium channel beta1A subunits.
2000,
Pubmed
Konno,
Isolation and structure of pompilidotoxins, novel peptide neurotoxins in solitary wasp venoms.
1998,
Pubmed
Langer,
Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7.
2008,
Pubmed
Lenkowski,
Lidocaine block of neonatal Nav1.3 is differentially modulated by co-expression of beta1 and beta3 subunits.
2003,
Pubmed
,
Xenbase
Li,
Mutations of the SCN4B-encoded sodium channel β4 subunit in familial atrial fibrillation.
2013,
Pubmed
Liu,
Crystal structure of the extracellular domain of human myelin protein zero.
2012,
Pubmed
Lobo,
The deletion of exon 3 in the cardiac ryanodine receptor is rescued by β strand switching.
2011,
Pubmed
Makielski,
Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on alpha (hH1 vs. rSkM1) and beta 1 subunits.
1999,
Pubmed
,
Xenbase
Makita,
Molecular determinants of beta 1 subunit-induced gating modulation in voltage-dependent Na+ channels.
1996,
Pubmed
,
Xenbase
Marcotte,
Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels.
1997,
Pubmed
,
Xenbase
Marionneau,
The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K⁺ channels.
2012,
Pubmed
Martin,
Large scale purification of toxins from the venom of the scorpion Androctonus australis Hector.
1986,
Pubmed
McCormick,
Molecular determinants of Na+ channel function in the extracellular domain of the beta1 subunit.
1998,
Pubmed
,
Xenbase
McCoy,
Phaser crystallographic software.
2007,
Pubmed
Meadows,
Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1.
2002,
Pubmed
,
Xenbase
Medeiros-Domingo,
SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.
2007,
Pubmed
Middleton,
Two tarantula peptides inhibit activation of multiple sodium channels.
2002,
Pubmed
Morgan,
beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics.
2000,
Pubmed
,
Xenbase
Murshudov,
Refinement of macromolecular structures by the maximum-likelihood method.
1997,
Pubmed
Nettleship,
Methods for protein characterization by mass spectrometry, thermal shift (ThermoFluor) assay, and multiangle or static light scattering.
2008,
Pubmed
Nguyen,
Modulation of voltage-gated K+ channels by the sodium channel β1 subunit.
2012,
Pubmed
,
Xenbase
Ogiwara,
A homozygous mutation of voltage-gated sodium channel β(I) gene SCN1B in a patient with Dravet syndrome.
2012,
Pubmed
Oyama,
Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice.
2006,
Pubmed
Patino,
A functional null mutation of SCN1B in a patient with Dravet syndrome.
2009,
Pubmed
,
Xenbase
Patino,
Voltage-gated Na+ channel β1B: a secreted cell adhesion molecule involved in human epilepsy.
2011,
Pubmed
Qu,
Functional roles of the extracellular segments of the sodium channel alpha subunit in voltage-dependent gating and modulation by beta1 subunits.
1999,
Pubmed
,
Xenbase
Rogers,
Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
1996,
Pubmed
Scheffer,
Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations.
2007,
Pubmed
Schreibmayer,
Mechanism of modulation of single sodium channels from skeletal muscle by the beta 1-subunit from rat brain.
1994,
Pubmed
,
Xenbase
Tan,
Sudden infant death syndrome-associated mutations in the sodium channel beta subunits.
2010,
Pubmed
Uebachs,
Efficacy loss of the anticonvulsant carbamazepine in mice lacking sodium channel beta subunits via paradoxical effects on persistent sodium currents.
2010,
Pubmed
Wallace,
Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B.
1998,
Pubmed
,
Xenbase
Watanabe,
Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.
2008,
Pubmed
Weiser,
Inhibition of tetrodotoxin (TTX)-resistant and TTX-sensitive neuronal Na(+) channels by the secretolytic ambroxol.
2002,
Pubmed
Wilson,
Navβ subunits modulate the inhibition of Nav1.8 by the analgesic gating modifier μO-conotoxin MrVIB.
2011,
Pubmed
,
Xenbase
Wimmer,
Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus.
2010,
Pubmed
Wong,
beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase.
2005,
Pubmed
Xiao,
The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation.
2010,
Pubmed
Yereddi,
The immunoglobulin domain of the sodium channel β3 subunit contains a surface-localized disulfide bond that is required for homophilic binding.
2013,
Pubmed
Yu,
Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2.
2003,
Pubmed
Zhang,
Co-expression of Na(V)β subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins.
2013,
Pubmed
,
Xenbase
Zhang,
The voltage-gated Na+ channel Nav1.8 contains an ER-retention/retrieval signal antagonized by the beta3 subunit.
2008,
Pubmed
Zhou,
Glycosylation of the sodium channel β4 subunit is developmentally regulated and involves in neuritic degeneration.
2012,
Pubmed
