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1.
海葵具有用于捕食和防御功能的触手刺细胞,其分泌的毒液主要包含蛋白和多肽类毒素,其中多肽神经毒素具有序列多样,结构稳定,靶点特异等特点。目前,已经从海葵中分离并鉴定了100余种多肽神经毒素,以电压门控钠离子通道(voltage-gated sodium channels,VGSCs)、电压门控钾离子通道(voltage-gated potassium channels,VGPCs)、酸敏感离子通道(acid-sensing ion channels,ASICs)等为主要作用靶点,它们已经成为研究特定离子通道的结构和功能的重要工具。本论文主要综述迄今为止从海葵中分离得到的海葵多肽神经毒素的类型、结构特征、药理活性以及临床应用。  相似文献   

2.
目的研究苯佐卡因(BZC)对大鼠背根神经节(DRG)神经元河豚毒素不敏感型(TTX-r)钠电流的影响,探讨其镇痛作用的机制。方法酶解法分离新生大鼠单个DRG神经元,应用全细胞膜片钳技术记录不同浓度BZC对TTX-r钠电流的影响。结果 BZC浓度依赖性静息阻断TTX-r钠电流,30、100和300μmol.L-1的BZC分别使TTX-r钠电流峰值抑制率达(18.83±8.51)%、(33.08±9.19)%、(58.91±12.02)%,并使TTX-r钠电流稳态失活曲线浓度依赖性向超极化方向移动。结论 BZC浓度依赖性阻断DRG神经元TTX-r钠离子通道并改变通道的失活,可能是其影响痛觉传导通路以及产生镇痛作用的机制之一。  相似文献   

3.
河豚毒素与钠离子通道的相互作用   总被引:1,自引:0,他引:1  
目前,从电鳐电器官、大鼠脑、大鼠肌纤维膜、鸡心脏等组织器官分离提取钠离子通道,开展结合特性、沉降系数、分子量以及大的亚单位的表现分子量等钠离子通道分子特性研究的报道很多。河豚毒素(TTX)、石房蛤毒素(STX)等神经毒素对钠离子通道具有很高的亲和力,是识别钠离子通道十分有效的工具药。经过对TTX结构的改造,定位氧化并与酪氨偶联后,采用Lodogen法标记成功地获高比度的125I标记的TTX,开展了125ITTX与电鳐电器官、大鼠脑、大鼠肌纤维膜、大鼠心脏的钠离子通道相互作用研究。将电鳐电器官、…  相似文献   

4.
目的 本文通过观察芍药苷(Paeoniflorin,Pae)对小鼠背根神经节(DRG)细胞电压门控河豚毒素敏感型(TTX-S)钠电流的影响,探讨芍药苷的镇痛机制。方法 应用全细胞膜片钳技术在急性分离背根神经节细胞上记录河豚毒素敏感型钠电流。结果 芍药苷浓度依赖地抑制河豚毒素敏感型钠电流,其半抑制浓度(IC50)为1 224.1 mmol·L-1。芍药苷1 mmol·L-1使河豚毒素敏感型钠通道的失活曲线向超极化方向转移约7.1 mV,并且延迟失活后通道的恢复,但对激活曲线没有影响。结论 芍药苷可能通过抑制河豚毒素敏感型钠通道,改变钠通道的动力学特征,从而发挥其镇痛作用。  相似文献   

5.
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。  相似文献   

6.
目的 初步观察草酸铂(抗肿瘤药)神经毒性的作用机制.方法 分离大鼠脊髓背根神经节神经元细胞,用膜片钳法分别检测草酸铂细胞外和细胞内给药时,神经元细胞膜七钠离子通道电流的变化.结果 在给药5、10、15 min,与给药前比较,钠离子电流振幅大、中、小细胞都有明显降低(P<0.05);小细胞给药后不同时间点的钠离子电流振幅抑制率明显大于同期大、中细胞的抑制率,其对小细胞的抑制作用明显高于大细胞和中细胞(P<0.05).结论 草酸铂对神经元细胞膜上电压门控钠离子通道的抑制可能是其神经毒性作用机制;背根神经节小细胞可能与草酸铂神经毒性症状的产生关系较密切.  相似文献   

7.
海葵Radianthus macrodactylus:皮群海葵毒素的一种新来源   总被引:1,自引:0,他引:1  
Mahn.  VM 《中国海洋药物》1995,14(4):52-52
海葵是季胺盐(四乙胺、黄海葵素)、生物胺(组胺、5—HT、多巴胺)、多肽(神经毒素、心脏毒素、蛋白酶抑制剂)以及蛋白质(细胞毒素、酶)等生物活性物质的丰富来源。在过去10年中,有关多肽神经毒素选择性地作用于兴奋膜的钠通道的课题一直为研究者所关注。 近几年,作者致力于研究海葵Radianthus macrodactylus产生的同源性神  相似文献   

8.
目的:比较局麻药罗哌卡因和布比卡因对大鼠背根神经节(DRG)河豚毒素(TTX)敏感(TTX-S)和TTX不敏感(TTX-R)的钠通道阻滞作用的差别,探讨罗哌卡因麻醉时产生感觉运动分离的可能机制。方法:急性分散大鼠背根神经节细胞,利用全细胞膜片钳技术记录DRG细胞TTX-S和TTX-R钠电流,通过浴槽内给药,观察罗哌卡因和布比卡因对TTX-S和TTX-R钠电流的作用。结果:TTX-S钠电流主要产生于大的DRG细胞,而TTX-R钠电流主要产生于小的DRG细胞;罗哌卡因对TTX-R钠电流的半数抑制浓度(IC50)为65.7±6.1μmol·L-1,远低于其对TTX-S钠电流的IC50(246.8±11.2μmol·L-1,P<0.01);布比卡因对TTX-R和TTX-S钠电流的IC50值基本相同(27.2±6.2μmol·L-1vs29.5±2.9μmol·L-1,P>0.05)。结论:罗哌卡因优先阻滞TTX-R钠通道,对TTX-R钠通道和TTX-S钠通道的选择性阻滞是其硬膜外麻醉时感觉运动分离的原因之一。  相似文献   

9.
海葵素结构功能与基因工程的研究现状与进展   总被引:2,自引:0,他引:2  
对海葵素(anthopleurin)的深入研究,起始于1976年美国夏威夷大学Shibata等人的工作。他们从黄海葵(Anthopleuraxathogrammica)分离纯化了AP-A和AP-B_2种毒素,发现有增强心肌收缩的作用,其效力大大强于毒毛旋花苷G,因此被认为是一个治疗心衰的极有潜力的药物。1977年又报道从华丽海葵(Anthopleuraelegantissima)得到AP-C素,同样具有增强心肌收缩作用。Tanaka等人相继研究证实3  相似文献   

10.
黄云  张诗嘉  张路路  刘文涛  张广钦 《药学研究》2018,37(8):435-438,465
目的 通过观察和厚朴酚(honokiol, Hon)对河豚毒素不敏感(TTX-R)钠电流的作用,探讨它可能的镇痛机制。方法 应用酶解法急性分离小鼠背根神经节细胞,全细胞膜片钳技术记录河豚毒素不敏感钠电流。结果 和厚朴酚对河豚毒素不敏感钠电流的抑制呈现浓度依赖性,半抑制浓度(IC50)为28.1 μmol·L-1。和厚朴酚(30 μmol·L-1)使河豚毒素不敏感钠电流密度下降48.1%,稳态激活和失活曲线分别向右和左偏移约7 mV和11.1 mV,但不影响通道的恢复时间。结论 和厚朴酚明显抑制河豚毒素不敏感钠电流,其作用可能与它的镇痛机制有关。  相似文献   

11.
A new peptide toxin exhibiting a molecular weight of 5043Da (av.) and comprising 47 amino acid residues was isolated from the sea anemone Condylactis gigantea. Purification of the peptide was achieved by a multistep chromatographic procedure monitoring its strong paralytic activity on crustacea (LD(50) approx. 1microg/kg). Complete sequence analysis of the toxic peptide revealed the isolation of a new member of type I sea anemone sodium channel toxins containing the typical pattern of the six cysteine residues. From 11kg of wet starting material, approximately 1g of the peptide toxin was isolated. The physiological action of the new toxin from C. gigantea CgNa was investigated on sodium currents of rat dorsal root ganglion neurons in culture using whole-cell patch clamp technique (n=60). Under current clamp condition (CgNa) increased action potential duration. This effect is due to slowing down of the TTX-S sodium current inactivation, without modifying the activation process. CgNa prolonged the cardiac action potential duration and enhanced contractile force albeit at 100-fold higher concentrations than the Anemonia sulcata toxin ATXII. The action on sodium channel inactivation and on cardiac excitation-contraction coupling resemble previous results with compounds obtained from this and other sea anemones [Shapiro, B.I., 1968. Purification of a toxin from tentacles of the anemone C. gigantea. Toxicon 5, 253-259; Pelhate, M., Zlotkin, E., 1982. Actions of insect toxin and other toxins derived from the venom of scorpion Androtonus australis on isolated giant axons of the cockroach Periplaneta americana. J. Exp. Biol. 97, 67-77; Salgado, V., Kem, W., 1992. Actions of three structurally distinct sea anemone toxins on crustacean and insect sodium channels. Toxicon 30, 1365-1381; Bruhn, T., Schaller, C., Schulze, C., Sanchez-Rodriquez, J., Dannmeier, C., Ravens, U., Heubach, J.F., Eckhardt, K., Schmidtmayer, J., Schmidt, H., Aneiros, A., Wachter, E., Béress, L., 2001. Isolation and characterization of 5 neurotoxic and cardiotoxic polypeptides from the sea anemone Anthopleura elegantissima. Toxicon, 39, 693-702]. Comprehensive analysis of the purified active fractions suggests that CgNa may represent the main peptide toxin of this sea anemone species.  相似文献   

12.
Kazuo Shiomi 《Toxicon》2009,54(8):1112-546
Sea anemones are a rich source of peptide toxins acting on ion channels. Two classes of peptide toxins, site-3 sodium channel toxins and Kv1 potassium channel toxins, have been well characterized and some of them used as valuable pharmacological reagents. Recently, the following six peptides toxins, which structurally constitute a new family but target different ion channels, have been isolated: BDS-I and -II (Kv3 potassium channel toxins) from Anemonia sulcata, APETx1 (human ether-a-go-go-related gene potassium channel toxin) and APETx2 (acid-sensing sodium channel toxin) from Anthopleura elegantissima, BcIV (sodium channel toxin) from Bunodosoma caissarum and Am II (whose target is unknown) from Antheopsis maculata. In addition, the following structurally novel peptide toxins have also emerged in sea anemones: gigantoxin I (epidermal growth factor-like toxin) from Stichodactyla gigantea and acrorhagins I and II from acrorhagi (specialized aggressive organs) of Actinia equina. This review deals with the structural and functional features of these recently isolated sea anemone peptide toxins that are promising tools in studying the physiology of diverse ion channels.  相似文献   

13.
This paper describes the interaction of several polypeptide neurotoxins isolated from sea anemone toxins and scorpion venom with the tetrodotoxin-resistant Na+ channel of rat cardiac cells. The 22Na+ flux and tension development were measured to examine in parallel the cardiotonic and cardiotoxic effects of these polypeptides. Inotropic effects and arrhythmias were seen in the concentration range in which an action of the toxins on the Na+ channel was observed. The maximal inotropic effect was systematically observed at toxin concentrations below the concentration value observed for half-maximal stimulation of 22Na+ flux through the Na+ channel. Arrhythmias began at concentrations near the value for half-maximal stimulation of 22Na+ flux by the toxins. Toxins extracted from the sea anemones Anemonia sulcata and Anthopleura xanthogrammica were more active than scorpion toxins and sea anemone Radianthus paumotensis toxins. The most interesting among all the toxins tested for potential use in cardiotherapy was toxin II from Anthopleura xanthogrammica.  相似文献   

14.
海葵毒素anthopleurin—Q对豚鼠心室肌细胞钠电流的作用   总被引:4,自引:0,他引:4  
目的:研究从海葵(Anthopleura xanthogrammica)提取的毒素anthopleurin-Q(AP-Q)对豚鼠心室肌钠电流(I_(Na))的作用。方法:用酶消化法分离豚鼠单个心室肌细胞,用全细胞膜片箝技术记录心室肌细胞钠电流。结果:AP-Q 3-30nmol/L浓度依赖性地增大I_(Na),EC_(50)、为104nmol/L(95%可信范围:78-130nmol/L)。AP-Q 300nmol/L使I-V曲线左移,使半数激活电压从(-36.3±2.3)mV变为(-43±23)mV(n=6,P<0.01),半数失活电压从(-75±6)mV变为(-59±5)mV(n=6,P<0.01)。AP-Q 300nmol/L使I_(Na)半数恢复时间从(114±36)ms缩短为(17±2)ms(n=6,P<0.01),并明显减慢I_(Na)的快速失活时间常数(τ_f)。结论:AP-Q对I_(Na)有促进作用并减慢其失活过程。  相似文献   

15.
Three peptide toxins (Am I-III) with crab toxicity were isolated from the sea anemone Anthopleura maculata by gel filtration and reverse-phase HPLC. Am I was weakly lethal to crabs (LD50 830 microg/kg) and Am III was potently lethal (LD50 70 microg/kg), while Am II was only paralytic (ED50 420 microg/kg). The complete amino acid sequences of the three toxins were determined by cDNA cloning based on 3'-Race and 5'-Race. Although Am III (47 residues) is an analogue of the well-known type 1 sea anemone sodium channel toxins, both Am I (27 residues) and II (46 residues) are structurally novel peptide toxins. Am I is a new toxin having no sequence homologies with any toxins. Am II shares 28-39% identity with the recently characterized sea anemone toxins inhibiting specialized ion channels, BDS-I and II from Anemonia sulcata and APETx1 and 2 from Anthopleura elegantissima. The precursor proteins of the three toxins are commonly composed of a signal peptide, a propart with a pair of basic residues (Lys-Arg) at the end and the remaining portion. Very interestingly, the Am I precursor protein contains as many as six copies of Am I.  相似文献   

16.
We have recently isolated a peptide neurotoxin, Jingzhaotoxin-I (JZTX-I), from Chinese tarantula Chilobrachys jingzhao venom that preferentially inhibits cardiac sodium channel inactivation and may define a new subclass of spider sodium channel toxins. In this study, we found that in contrast to other spider sodium channel toxins acting presynaptically rather than postsynaptically, JZTX-I augmented frog end-plate potential amplitudes and caused an increase in both nerve mediated and unmediated muscle twitches. Although JZTX-I does not negatively shift sodium channel activation threshold, an evident increase in muscle fasciculation was detected. In adult rat dorsal root ganglion neurons JZTX-I (1 microM) induced a significant sustained tetrodotoxin-sensitive (TTX-S) current that did not decay completely during 500 ms and was inhibited by 0.1 microM TTX or depolarization due to voltage-dependent acceleration of toxin dissociation. Moreover, JZTX-I decreased closed-state inactivation and increased the rate of recovery of sodium channels, which led to an augmentation in TTX-S ramp currents and decreasing the amount of inactivation in a use-dependant manner. Together, these data suggest that JZTX-I acted both presynaptically and postsynaptically and facilitated the neurotransmitter release by biasing the activities of sodium channels towards open state. These actions are similar to those of scorpion alpha-toxin Lqh II.  相似文献   

17.
The sea anemone polypeptide anthopleurin-A (AP-A) at nanomolar concentrations enhances myocardial contractility without affecting automaticity. It has a therapeutic index higher than that of the digitalis glyco-sides, and may serve as a molecular model for designing a new class of inotropic drugs acting on the myocardial Na channel at site 3. AP-A is a 49 residue peptide crosslinked by three disulfide bonds; its tertiary structure has been determined by NMR. Here we report the solid-phase synthesis of this polypeptide. Synthetic AP-A displayed CD and NMR spectra identical with those of the natural toxin; it possessed 94±15% of the inotropic activity of natural AP-A. Therefore, it is feasible to prepare various type 1 sea anemone toxin analogs by solid-phase chemical synthesis in order to identify side chains important for peptide folding and interaction with sodium channels.  相似文献   

18.
Ca2+ channel currents were recorded from cultured rat dorsal root ganglion neurons and cerebellar granule cells using the whole-cell recording variant of the patch clamp technique. omega-Aga-IA, a toxin purified from the venom of the American funnel web spider, Agelenopsis aperta, markedly inhibited high threshold barium currents (lBa) when applied at 10 nM concentration. The low threshold T-type current activated at Vc = -30 mV and the outward (Ca2+ channel) current activated at +120 mV were significantly less sensitive to omega-Aga-IA, omega-Conotoxin GVIA (1 microM) inhibited IBa irreversibly. In contrast, the action of omega-Aga-IA was partially reversed 5 min after its removal. The voltage-activated calcium current (ICa) was inhibited by omega-Aga-IA in a manner different from IBa. ICa measured at the end of a 100-msec voltage step command was reduced to a greater extent than the peak current. The residual ICa following application of omega-Aga-IA was a fast transient current. omega-Aga-IA did not inhibit voltage-activated sodium currents from dorsal root ganglion neurons in the absence of tetrodotoxin. omega-Aga-IA abolished the dihydropyridine (+)-202-791-sensitive L-type current component of IBa. We conclude that omega-Aga-IA is a very potent inhibitor of neuronal voltage-activated Ca2+ channel currents and that it may prove to be a useful tool in the characterization and isolation of Ca2+ channels.  相似文献   

19.
Crotamine is a peptide toxin from the venom of the rattlesnake Crotalus durissus terrificus that induces a typical hind-limb paralysis of unknown nature. Hind limbs have a predominance of fast-twitching muscles that bear a higher density of sodium channels believed until now to be the primary target of crotamine. Hypothetically, this makes these muscles more sensitive to crotamine and would explain such hind-limb paralysis. To challenge this hypothesis, we performed concentration vs. response curves on fast (extensor digitorum longus (EDL)) and slow (soleus) muscles of adult male rats. Crotamine was tested on various human Na+ channel isoforms (Na(v)1.1-Na(v)1.6 alpha-subunits) expressed in HEK293 cells in patch-clamp experiments, as well as in acutely dissociated dorsal root ganglion (DRG) neurons. Also, the behavioral effects of crotamine intoxication were compared with those of a muscle-selective sodium channel antagonist mu-CgTx-GIIIA, and other sodium-acting toxins such as tetrodotoxin alpha- and beta-pompilidotoxins, sea anemone toxin BcIII, spider toxin Tx2-6. Results pointed out that EDL was more susceptible to crotamine than soleus under direct electrical stimulation. Surprisingly, electrophysiological experiments in human Na(v)1.1 to Na(v)1.6 Na+ channels failed to show any significant change in channel characteristics, in a clear contrast with former studies. DRG neurons did not respond to crotamine. The behavioral effects of the toxins were described in detail and showed remarkable differences. We conclude that, although differences in the physiology of fast and slow muscles may cause the typical crotamine syndrome, sodium channels are not the primary target of crotamine and therefore, the real mechanism of action of this toxin is still unknown.  相似文献   

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