作用于电压门控钠离子通道的芋螺毒素研究进展

电压门控钠离子(Na+)通道(VGSCs)对兴奋细胞动作电位具有调节作用,许多生物毒素能与VGSCs相互作用。近年来研究发现,热带海洋肉食性软体动物芋螺中含有多种多肽类毒素(芋螺毒素或芋螺肽),其中一大类芋螺毒素能与Na+通道各种亚型特异结合,改变Na+通道的功能,对于研究Na+通道的结构和功能以及研发作用于Na+通道的相关药物或其先导化合物具有重要作用。本文就近年来发现的作用于Na+通道的芋螺毒素的研究进展进行综述。     

作用于电压门控离子通道的芋螺毒素研究进展

目的芋螺毒素是一类具有独特药理活性的海洋生物毒素,能高度特异性地作用于各类电压门控和配体门控离子通道及受体,已成为药理学和神经科学研究的一种有力工具和新药开发的重要来源。本文介绍了作用于各种电压门控离子通道的芋螺毒素的研究现状及其应用情况。     

电压门控钠离子通道与肿瘤

目的综述电压门控钠离子通道(voltage-gated sodium channels,VGSCs)在不同肿瘤发生、发展过程中的作用。方法根据已有的关于电压门控钠离子通道在不同肿瘤细胞中的表达有所不同,阐述VGSC与不同类型肿瘤发生、发展的相关性。结果侵袭性较强的肿瘤细胞中一般有特异性的VGSCα亚基的表达,而相应的侵袭性较弱的细胞中则无VGSC的表达。结论VGSC在肿瘤细胞中的异常表达,可作为治疗靶点而进行相关药物的开发和临床应用。     

电压门控钙离子通道的研究进展

电压门控钙离子通道(voltage-gated calcium channel)是一种镶嵌于细胞膜上的大分子蛋白复合体,其中央是高度选择性的亲水通道,允许适当电荷和适当大小的钙离子通过.钙离子通道广泛分布于机体的脑、心脏、平滑肌以及内分泌细胞等组织中,并在基因表达、肌肉收缩和荷尔蒙的释放等生命活动中扮演着重要角色.本文就电压门控钙离子通道的基因编码、生理分布及空间结构的研究进展综述如下.     

电压门控钠通道在慢性疼痛药物发现中的研究进展

由于发病率高、药物效果有限或治疗药物受限等原因,慢性疼痛的治疗一直是世界范围内研究人员关注的难题。电压门控钠通道( VGSCs)阻滞剂有较为显著的镇痛作用,目前已知与慢性疼痛相关的钠通道亚型主要有 Nav1.3、Nav1.7、Nav1.8、 Nav1.9。2021年 8—9月进行了该研究,全面概括了上述钠通道亚型与慢性疼痛的关系,归纳出潜在候选药物临床前研究方法,以及已被证实安全有效的选择性钠通道阻滞剂品种,为选择性钠通道阻滞剂的开发提供参考。     

电压门控钙离子通道药物研究进展

电压门控钙离子通道家族（VGCC）是细胞表面一类重要的信号转换器,它能够将膜电势转变成局部胞内钙离子瞬时变化,从而启动许多重要的生理活动,例如肌肉收缩、激素分泌、神经传递和基因表达。VGCC表达和功能的异常与高血压、心绞痛、心律失常、疼痛、癫痫和帕金森病等疾病的发生有很大关系。近年来,以VGCC为靶点的药物在临床上表现出良好的治疗效果和较小的不良反应,具有较好的应用前景。综述VGCC的结构、功能以及相关药物研究进展,以期为与VGCC相关的药物开发提供参考。     

电压门控钠离子通道与疼痛

目的综述电压门控钠离子通道(voltage-gated sodium channels,VGSCs)与疼痛发生发展的相关性。方法根据已有的介绍电压门控钠离子通道与疼痛的文献共29篇,叙述不同α亚基与辅助亚基(β亚基)在疼痛发生与维持中的作用。结果特异性表达在外周神经系统中的钠离子通道NaV1.7、NaV1.8和NaV1.9,以及只在哺乳动物胚胎时期或神经元损伤后表达水平上调的NaV1.3与疼痛密切相关。结论 疼痛相关的电压门控钠离子通道亚型可作为疼痛性疾病治疗的药物筛选靶点。     

电压门控性钠通道亚型和神经病理性疼痛

神经病理性疼痛是神经系统损伤引起的一种慢性疼痛。感觉神经元上的电压门控性钠通道在多种由外周神经损伤引起的神经病理性疼痛中具有重要的作用。近年来,随着对钠通道亚型在神经病理性疼痛发病机制中作用的阐明,发展特异性的钠通道亚型阻断药物将成为治疗神经病理性疼痛的重要研究方向。     

若干临床疾病与电压门控钠通道的特异调控

电压门控钠通道在细胞电兴奋活动中起着至关重要的调控作用.自19世纪40年代,Hodgkin等[1]首次定性地鉴定了兴奋性细胞膜钠通道的电生理活动特征,相当一段时期内,对钠通道分型的认识似乎主要依据其对河豚毒素(TTX)的药理敏感性,即TTX-敏感型(TTX-S)或TTX-非敏感型(TTX-R)钠通道.     

电压门控钠通道亚型及相关疾病的研究进展

目的综述近年国内外电压门控钠通道亚型及相关疾病的研究新进展,为今后相关疾病的诊断和治疗提供理论依据。方法通过检索国内外相关文献,从钠通道的类别、亚型及相关疾病等方面进行综述。结果钠通道的主要作用是参与动作电位的形成和信号传导,临床许多疾病的发生和发展与钠离子通道的改变有关。钠通道结构或功能异常通常会导致如心血管系统、神经系统和肌肉等相关疾病的发生。结论不同类型的钠通道在机体生理病理过程中的不同环节发挥着不同的作用,近期研究取得了很大进展,其在相关疾病诊断和治疗方面的应用前景值得期待。     

Insect-selective spider toxins targeting voltage-gated sodium channels.

The voltage-gated sodium (Na(v)) channel is a target for a number of drugs, insecticides and neurotoxins. These bind to at least seven identified neurotoxin binding sites and either block conductance or modulate Na(v) channel gating. A number of peptide neurotoxins from the venoms of araneomorph and mygalomorph spiders have been isolated and characterized and determined to interact with several of these sites. These all conform to an 'inhibitor cystine-knot' motif with structural, but not sequence homology, to a variety of other spider and marine snail toxins. Of these, spider toxins several show phyla-specificity and are being considered as lead compounds for the development of biopesticides. Hainantoxin-I appears to target site-1 to block Na(v) channel conductance. Magi 2 and Tx4(6-1) slow Na(v) channel inactivation via an interaction with site-3. The delta-palutoxins, and most likely mu-agatoxins and curtatoxins, target site-4. However, their action is complex with the mu-agatoxins causing a hyperpolarizing shift in the voltage-dependence of activation, an action analogous to scorpion beta-toxins, but with both delta-palutoxins and mu-agatoxins slowing Na(v) channel inactivation, a site-3-like action. In addition, several other spider neurotoxins, such as delta-atracotoxins, are known to target both insect and vertebrate Na(v) channels most likely as a result of the conserved structures within domains of voltage-gated ion channels across phyla. These toxins may provide tools to establish the molecular determinants of invertebrate selectivity. These studies are being greatly assisted by the determination of the pharmacophore of these toxins, but without precise identification of their binding site and mode of action their potential in the above areas remains underdeveloped.     

Spider-venom peptides that target voltage-gated sodium channels: Pharmacological tools and potential therapeutic leads

Voltage-gated sodium (Na_V) channels play a central role in the propagation of action potentials in excitable cells in both humans and insects. Many venomous animals have therefore evolved toxins that modulate the activity of Na_V channels in order to subdue their prey and deter predators. Spider venoms in particular are rich in Na_V channel modulators, with one-third of all known ion channel toxins from spider venoms acting on Na_V channels. Here we review the landscape of spider-venom peptides that have so far been described to target vertebrate or invertebrate Na_V channels. These peptides fall into 12 distinct families based on their primary structure and cysteine scaffold. Some of these peptides have become useful pharmacological tools, while others have potential as therapeutic leads because they target specific Na_V channel subtypes that are considered to be important analgesic targets. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides and so far only 0.01% of this diversity been characterised. Thus, it is likely that future research will reveal additional structural classes of spider-venom peptides that target Na_V channels.     

Therapeutic potential of peptide toxins that target ion channels

Traditional healthcare systems in China, India, Greece and the Middle East have for centuries exploited venomous creatures as a resource for medicines. This review focuses on one class of pharmacologically active compounds from venom, namely peptide toxins that target ion channels. We highlight their therapeutic potential and the specific channels they target. The field of therapeutic application is vast, including pain, inflammation, cancer, neurological disorders, cardioprotection, and autoimmune diseases. One of these peptides is in clinical use, and many others are in various stages of pre-clinical and clinical development.     

Animal toxins acting on voltage-gated potassium channels

Animal venoms are rich natural sources of bioactive compounds, including peptide toxins acting on the various types of ion channels, i.e. K(+), Na(+), Cl(-) and Ca(2+). Among K+ channel-acting toxins, those selective for voltage-gated K(+) (Kv) channels are widely represented and have been isolated from the venoms of numerous animal species, such as scorpions, sea anemones, snakes, marine cone snails and spiders. The toxins characterized hitherto contain between 22 and 60 amino acid residues, and are cross-linked by two to four disulfide bridges. Depending on their types of fold, toxins can be classified in eight structural categories, which showed a combination of beta-strands, helices, or a mixture of both. The main architectural motifs thereof are referred to as alpha/beta scaffold and inhibitor cystine knot (ICK). A detailed analysis of toxin structures and pharmacological selectivities indicates that toxins exhibiting a similar type of fold can exert their action on several subtypes of Kv channels, whereas a particular Kv channel can be targeted by toxins that possess unrelated folds. Therefore, it appears that the ability of structurally divergent toxins to interact with a particular Kv channel relies onto a similar spatial distribution of amino acid residues that are key to the toxin-channel interaction (rather than the type of toxin fold). The diversity of Kv channel blockers and their therapeutic value in the potential treatment of a number of specific human diseases, especially autoimmune disorders, inflammatory neuropathies and cancer, are reviewed.     

Gating modifier toxins of voltage-gated calcium channels.

Some of the most potent and specific inhibitors of voltage-gated calcium channels are peptide toxins that inhibit channel function not by occlusion of the channel pore, but rather by interfering with the voltage dependence and kinetics of channel opening and closing. Many such gating modifier toxins conform to the inhibitor cystine knot structural family and have primary sequence or functional mechanism similar to toxins that target voltage-gated sodium or potassium channels. This review introduces known gating modifiers of calcium channels, discusses the selectivity, binding sites, and mechanism of the toxin-channel interaction, and reviews the usefulness of these toxins as research tools and as the basis for novel calcium channel pharmacology and therapeutics.     

Subtype-selective targeting of voltage-gated sodium channels

Voltage-gated sodium channels are key to the initiation and propagation of action potentials in electrically excitable cells. Molecular characterization has shown there to be nine functional members of the family, with a high degree of sequence homology between the channels. This homology translates into similar biophysical and pharmacological properties. Confidence in some of the channels as drug targets has been boosted by the discovery of human mutations in the genes encoding a number of them, which give rise to clinical conditions commensurate with the changes predicted from the altered channel biophysics. As a result, they have received much attention for their therapeutic potential. Sodium channels represent well-precedented drug targets as antidysrhythmics, anticonvulsants and local anaesthetics provide good clinical efficacy, driven through pharmacology at these channels. However, electrophysiological characterization of clinically useful compounds in recombinant expression systems shows them to be weak, with poor selectivity between channel types. This has led to the search for subtype-selective modulators, which offer the promise of treatments with improved clinical efficacy and better toleration. Despite developments in high-throughput electrophysiology platforms, this has proven very challenging. Structural biology is beginning to offer us a greater understanding of the three-dimensional structure of voltage-gated ion channels, bringing with it the opportunity to do real structure-based drug design in the future. This discipline is still in its infancy, but developments with the expression and purification of prokaryotic sodium channels offer the promise of structure-based drug design in the not too distant future.     

The action of toxins on the voltage-gated sodium channel

The author discusses the recent findings concerning the influence of selected neurotoxins on the voltage-gated sodium channel. Sodium voltage-gated channels are blocked or modified by four of five classes of neurotoxical agents: guanidinum toxins (tetrodotoxin, saxitoxin), lipid soluble compounds (veratridine, grayanotoxin, batrachotoxin, aconitine, pyrethroids, brevetoxins), polipeptide toxins (alpha-scorpion and sea anemone toxins) and beta-scorpion toxins. The mode of operation of these toxins at the different binding sites within the channel is discussed.     

Mammalian skeletal muscle voltage-gated sodium channels are affected by scorpion depressant "insect-selective" toxins when preconditioned

Among scorpion beta- and alpha-toxins that modify the activation and inactivation of voltage-gated sodium channels (Na(v)s), depressant beta-toxins have traditionally been classified as anti-insect selective on the basis of toxicity assays and lack of binding and effect on mammalian Na(v)s. Here we show that the depressant beta-toxins LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus (Lqh) bind with nanomolar affinity to receptor site 4 on rat skeletal muscle Na(v)s, but their effect on the gating properties can be viewed only after channel preconditioning, such as that rendered by a long depolarizing prepulse. This observation explains the lack of toxicity when depressant toxins are injected in mice. However, when the muscle channel rNa(v)1.4, expressed in Xenopus laevis oocytes, was modulated by the site 3 alpha-toxin LqhalphaIT, LqhIT2 was capable of inducing a negative shift in the voltage-dependence of activation after a short prepulse, as was shown for other beta-toxins. These unprecedented results suggest that depressant toxins may have a toxic impact on mammals in the context of the complete scorpion venom. To assess whether LqhIT2 and Lqh-dprIT3 interact with the insect and rat muscle channels in a similar manner, we examined the role of Glu24, a conserved "hot spot" at the bioactive surface of beta-toxins. Whereas substitutions E24A/N abolished the activity of both LqhIT2 and Lqh-dprIT3 at insect Na(v)s, they increased the affinity of the toxins for rat skeletal muscle channels. This result implies that depressant toxins interact differently with the two channel types and that substitution of Glu24 is essential for converting toxin selectivity.