Localization of Receptor Site on Insect Sodium Channel for Depressant β-toxin BmK IT2

He, Huiqiong; Liu, Zhirui; Dong, Bangqian; Zhang, Jianwei; Shu, Xueqin; Zhou, Jingjing; Ji, Yonghua

doi:10.1371/journal.pone.0014510

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…Nevertheless, these non-functional contact points can also be a requirement for the full activity of the toxin. He et al ( 2011 ) recently described this for binding of BmK IT2, a site 4 insect β-toxin from Buthus martensii Karsch, to insect DmNa v VGSCs. Mutations in the site 4 binding area (DII S3–S4) largely abolished the functional action of BmK IT2 on DmNa v .…”

Section: Revision Of Neurotoxin Binding Sitesmentioning

confidence: 98%

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Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

Stevens¹,

Peigneur²,

Tytgat³

2011

Front. Pharmacol.

251

209

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Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called “channelopathies.” The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. These concepts still form the basis for understanding the function of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and consequently generate a massive influx of sodium ions. Immediately after, channels will start to inactivate and currents decrease. In the inactivated state, channels stay refractory for new stimuli and they must return to the closed state before being susceptible to a new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our today’s understanding of the structure and function of ion channels and of VGSCs specifically. Moreover, neurotoxins acting on ion channels turned out to be valuable lead compounds in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt®, Elan). The original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now FDA/EMA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in pain fibers. This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the structure and function of VGSC and their potential as novel lead compounds in drug development.

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Section: Revision Of Neurotoxin Binding Sitesmentioning

confidence: 98%

“…However, some anchor points in DIII turned out to be responsible for the selective recognition of the insect channel over the rat Na v 1.2 channel. In addition, the N-terminal part of the S5–S6 linker (SS2–S6) in this DIII greatly influenced the potency of the BmK IT2 binding to DmNa v (He et al, 2011 ).…”

Section: Revision Of Neurotoxin Binding Sitesmentioning

confidence: 99%

Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

Stevens¹,

Peigneur²,

Tytgat³

2011

Front. Pharmacol.

251

209

View full text Add to dashboard Cite

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“…The patch-clamp experiment also proved that BmK IT2 can inhibit the persistent sodium current of hippocampal pyramidal neurons [59]. However, previous studies have found that BmK IT2 had no significant inhibitory effect on the peak Na + currents of Nav1.2, 1.3, and 1.6 heterologous-expressed in oocytes [51]. It is suggested that BmK IT2 might act on Nav1.1 or Nav1.7 in the central nervous system (CNS).…”

Section: Antiepileptic Activity Of Bmk Toxins 31 Antiepileptic Activmentioning

confidence: 93%

“…In fact, the inhibition of BmK IT2 on total Na + currents was observed in small DRG neurons [13]. By testing VGSC subtypes in Xenopus oocytes expression system, Nav1.2, Nav1.3, and Nav1.6 display insensitive property to BmK IT2, suggesting that other isoforms, especially Nav1.7-1.9, might be involved in the suppressive activity of BmK IT2 in rat pathological models [51]. The results illuminated that BmK IT2 can be developed as a novel analgesic peptide with therapeutic potential.…”

Section: Analgesic Effects Of Bmk Toxins Against Vgscsmentioning

confidence: 99%

Scorpion Toxins from Buthus martensii Karsch (BmK) as Potential Therapeutic Agents for Neurological Disorders: State of the Art and Beyond

Wang¹,

Zhang²,

Zhu³

et al. 2021

Medical Toxicology

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Scorpions are fascinating creatures which became residents of the planet well before human beings dwelled on Earth. Scorpions are always considered as a figure of fear, causing notable pain or mortality throughout the world. Their venoms are cocktails of bioactive molecules, called toxins, which are responsible for their toxicity. Fortunately, medical researchers have turned the life-threatening toxins into life-saving therapeutics. From Song Dynasty in ancient China, scorpions and their venoms have been applied in traditional medicine for treating neurological disorders, such as pain, stroke, and epilepsy. Neurotoxins purified from Chinese scorpion Buthus Martensii Karsch (BmK) are considered as the main active ingredients, which act on membrane ion channels. Long-chain toxins of BmK, composed of 58-76 amino acids, could specifically recognize voltage-gated sodium channels (VGSCs). Short-chain BmK toxins, containing 28-40 amino acids, are found to modulate the potassium or chloride channels. These components draw attention as useful scaffolds for drug-design in order to tackle the emerging global medical threats. In this chapter, we aim to summarize the most promising candidates that have been isolated from BmK venoms for drug development.

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“…Analysis of subsequent DmNa v 1 mutants further highlighted that, in addition to the contribution of E896, L899, and G904 in DII S4 for functional action of BmK IT2, residues in DIII pore loop, esp. I1529 and R1530, were critical for recognition and binding of BmK IT2 (He et al 2011). Hence, DIII SS2-S6 is considered to be the recognition site with species selectivity for BmK IT2 and DII S3b-S4 is considered the functional voltage-trapping site of VGSCs.…”

Section: Pharmacological and Molecular Mechanisms Of Bmk Toxins Intermentioning

confidence: 99%

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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Localization of Receptor Site on Insect Sodium Channel for Depressant β-toxin BmK IT2

Cited by 14 publications

References 31 publications

Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

Scorpion Toxins from Buthus martensii Karsch (BmK) as Potential Therapeutic Agents for Neurological Disorders: State of the Art and Beyond

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

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