Molecular determination of selectivity of the site 3 modulator (BmK I) to sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-induced neuronal hyperexcitability

He, Huiqiong; Liu, ZhiRui; Dong, Bangqian; Zhou, Jingjing; Ji, Yonghua

doi:10.1042/bj20100517

Cited by 18 publications

(15 citation statements)

References 37 publications

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“…BmKM1 and OD1 are two examples tested for multiple channel isoforms, the former active on Na v 1.2, 1.3, 1.5, 1.6, and DmNa v 1 (32,43), and the latter affecting Na v 1.3, 1.5, 1.7, and DmNa v 1 (44,45). These two toxins were found to bind to the channels with differential affinities.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Diversification of Mesobuthus α-Scorpion Toxins Affecting Sodium Channels

Zhu

Peigneur

Gao

et al. 2012

Molecular & Cellular Proteomics

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␣-Scorpion toxins constitute a family of peptide modulators that induce a prolongation of the action potential of excitable cells by inhibiting voltage-gated sodium channel inactivation. Although they all adopt a conserved structural scaffold, the potency and phylogentic preference of these toxins largely vary, which render them an intriguing model for studying evolutionary diversification among family members. Here, we report molecular characterization of a new multigene family of ␣-toxins comprising 13 members (named MeuNaTx␣-1 to MeuNaTx␣-13) from the scorpion Mesobuthus eupeus. Of them, five native toxins (MeuNaTx␣-1 to -5) were purified to homogeneity from the venom and the solution structure of MeuNaTx␣ Venomous animals, such as sea anemones, scorpions, spiders, cone snails, jellyfish, and snakes, represent a distinct group of organisms that evolve toxins to help them capture prey and defend themselves from predators (1). These animals occupy diverse ecological niches and have different evolutionary histories and food sources, but they convergently select voltage-gated sodium channels (VGSCs) 1 as molecular targets for their toxins that can strongly modify VGSCs' functions to alter electrical excitability of an animal's neuromuscular system and thus cause rapid immobilization of both prey and competitors (2, 3). VGSCs play vital roles in the normal functioning of excitable tissues (neurons, muscles, and heart). These large, complex membrane proteins are composed of one principal ␣-subunit of 220 -260 kDa associated with one or more auxiliary ␤-subunits of ϳ33-36 kDa in some tissues of mammals and the tipE subunit in insects (4 -6). The ␣-subunit of VGSCs includes four homologous domains (DI-DIV) connected by intracellular and extracellular loops, each domain containing six helical transmembrane segments (S1-S6), and a hairpin-like P loop between S5 and S6 that forms the ion selectivity filter. Thus far, at least seven distinct receptor sites have been identified on the ␣-subunits for various animal-derived toxins that either affects ion permeation or voltage-dependent gating properties (7) 1 The abbreviations used are: VGSC, voltage-gated sodium channel; 3Ј-UTR, 3Ј-untranslational region; CS␣␤, cysteine-stabilized ␣-helical and ␤-sheet; MALDI-TOF MS, matrix-assisted laser desorption ionization time-of-flight mass spectrometry; MeuNaTx␣, Mesobuthus eupeus ␣-scorpion toxin; PSS, positively selected site; RACE, rapid amplification of cDNA end; RP-HPLC, reversed-phase high-performance liquid chromatography; TTX, tetrodotoxin. Research

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Section: Discussionmentioning

confidence: 99%

Evolutionary Diversification of Mesobuthus α-Scorpion Toxins Affecting Sodium Channels

Zhu

Peigneur

Gao

et al. 2012

Molecular & Cellular Proteomics

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“…The inactivation of Na + currents in rat-cultured hippocampal neurons was prolonged significantly by BmK I while the inactivation time and the peak amplitude of the currents from Na v 1.2 channels expressed in Xenopus laevis oocytes were both increased by BmK aIV (Chai et al 2006). Na v 1.6, one of the major contributors to neuronal firing in central nerve system, was found to be significantly modulated by BmK I through amplifying the persistent currents and prolonging the inactivation time course (He et al 2010).…”

Section: Epileptogenesis/anticonvulsion Of Bmk Toxinsmentioning

confidence: 94%

“…Moreover, BmK I could also accelerate the slow inactivation development and delayed recovery through binding to Na v 1.6/b1 in the open state; Na v 1.2/b1 was less affected with only increased fast time constants of inactivating current upon the application of BmK I at high concentration (500nM); and Na v 1.3a/b1 was nearly insensitive (He et al 2010). Residue-swap analysis verified that an acidic residue (e.g., Asp1602 in mNa v 1.6) within the domain IV S3-S4 extracellular loop of VGSCs was crucial for the selectivity and modulation pattern of BmK I, which was in agreement with other a-scorpion toxins binding to sodium channels (Zuo and Ji 2004;Bosmans and Tytgat 2007).…”

Section: Pharmacological and Molecular Mechanisms Of Bmk Toxins Intermentioning

confidence: 97%

Scorpion Venom Research Around The World: Chinese Scorpion Mesobuthus martensii Karsch

Liu¹,

Zr²,

Ji³

2013

Toxinology

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Scorpions, or "Quanxie" as named in traditional Chinese medical prescriptions, have long been exploited as remedy for expelling or relieving many disorders and syndromes, such as chronic pain, convulsions, cardiovascular diseases, or even tumors. In Chinese traditional medicine, the active part of scorpions is considered to be the tip of the tail containing a great reservoir of active components. However, it was not until recent decades that the pharmacological mechanisms of the venom and toxins of Chinese scorpion have been systematically studied. These toxins are known to be toxic polypeptides that specifically target membrane ion channels, through either enhancing the channel activity or suppressing the peak currents of channels, hereby drastically affecting the excitability of local neuronal circuits. Recent mapping of receptor sites of these toxins located on ion channels validates themselves as potential tools for probing and modulating the channel subtypes or gating properties involved in physiological/pathological conditions. While this chapter briefly covers the current knowledge regarding the traditional use of scorpions in traditional Chinese medicine, its main subject is the "state-of-the-art" view of physiological and pharmacological actions of neurotoxins found in the Chinese scorpion Mesobuthus martensii Karsch associated with ion channels, including nociceptive/antinociceptive effects, epileptic/antiepileptic functions, cardiovascular modulation, and antitumor effects. Meanwhile, the toxin-driven intracellular events parallel to behavioral phenotypes and the underlying linkage between structure and function of ion channels elucidated by molecular interactions with toxins will also be discussed.

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“…It was found that these toxins specifically bind to distinct regions on different VGSCs in either overlapped or separated forms, suggesting that binding sites on VGSCs are diverse (Jia et al, 1999;Li and Ji, 2000;Li et al, 2000aLi et al, , 2000bJi et al, 2002;Chai et al, 2006aChai et al, , 2006b. Also, key residues involved in toxin-channel inter-recognition or subtype-selective patterns were uncovered by site-directed mutagenesis (He et al, 2010(He et al, , 2011. These findings make BmK neurotoxins good candidates for probing the pharmacological and structural diversity of VGSCs in mammals or insects.…”

Section: Introductionmentioning

confidence: 95%

Exploring the obscure profiles of pharmacological binding sites on voltage-gated sodium channels by BmK neurotoxins

Liu

2011

Protein Cell

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Diverse subtypes of voltage-gated sodium channels (VGSCs) have been found throughout tissues of the brain, muscles and the heart. Neurotoxins extracted from the venom of the Asian scorpion Buthus martensi Karsch (BmK) act as sodium channel-specific modulators and have therefore been widely used to study VGSCs. α-type neurotoxins, named BmK I, BmK αIV and BmK abT, bind to receptor site-3 on VGSCs and can strongly prolong the inactivation phase of VGSCs. In contrast, β-type neurotoxins, named BmK AS, BmK AS-1, BmK IT and BmK IT2, occupy receptor site-4 on VGSCs and can suppress peak currents and hyperpolarize the activation kinetics of sodium channels. Accumulating evidence from binding assays of scorpion neurotoxins on VGSCs, however, indicate that pharmacological sensitivity of VGSC subtypes to different modulators is much more complex than that suggested by the simple α-type and β-type neurotoxin distinction. Exploring the mechanisms of possible dynamic interactions between site 3-/4-specific modulators and region- and/or species-specific subtypes of VGSCs would therefore greatly expand our understanding of the physiological and pharmacological properties of diverse VGSCs. In this review, we discuss the pharmacological and structural diversity of VGSCs as revealed by studies exploring the binding properties and cross-competitive binding of site 3- or site 4-specific modulators in VGSC subtypes in synaptosomes from distinct tissues of diverse species.

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Molecular determination of selectivity of the site 3 modulator (BmK I) to sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-induced neuronal hyperexcitability

Cited by 18 publications

References 37 publications

Evolutionary Diversification of Mesobuthus α-Scorpion Toxins Affecting Sodium Channels

Evolutionary Diversification of Mesobuthus α-Scorpion Toxins Affecting Sodium Channels

Scorpion Venom Research Around The World: Chinese Scorpion Mesobuthus martensii Karsch

Exploring the obscure profiles of pharmacological binding sites on voltage-gated sodium channels by BmK neurotoxins

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