User:Gurpjwair/sandbox
Anuroctoxin
For years there were only neurotoxins discovered which acted on either the sodium channels or the calcium channels. This changed in 1982 when it was discovered that a peptide in the venom of the scorpion Centruroides noxius inhibited potassium currents[1][2]. These discoveries of potassium channel inhibiting neurotoxins kept coming. One of them is the Anuroctoxin which is a peptide that is derived from the venom of the Mexican scorpion Anuroctonus phaiodactylus. This neurotoxin belongs to the alpha family of potassium channel acting peptides. It blocks especially the Kv1.3/KCNA3 channels, which it has a high affinity for[3].
Source[edit]
Anuroctoxin is a peptide which is derived from the scorpion Anuroctonus phaiodactylus, this scorpion belongs to the Iuridae family of scorpions.
Chemistry[edit]
The K+ channel acting peptides are grouped in three different families: the α-,β- and γ-scorpion toxins. These are collectively called the KTx’s ( K+ channel toxins)[4]. The Anuroctoxin peptide belongs to the α-KTx group[3] , these are short peptides which block potassium channels and consist of 30 to 40 amino acids with three or four disulfide bridges[5]. With use of phylogenetics it was analyzed in which subfamily of the α-KTx family the Anuroctoxin belongs too. This analyses showed that Anuroctoxin is included in subfamily six in the α-KTx phylogenetic tree, its systematic name is 6.12[3].
Structure[edit]
A 3D model of the Anuroctoxin, which was obtained with homology modeling and and molecular dynamics, showed that the Anuroctoxin is a peptide with 35 amino acid components with four disulfide bridges. The molecular weight of the Anuroctoxin was obtained with use of electrospray ionization which showed that this Anuroctoxin peptide has a molecular weight of 4082.8 Da[3].
Target[edit]
Patch-clamp experiments have shown that Anuroctoxin is a potent blocker of Kv1.3/KCNA3 (Kd= 0.73 nM) channels[3]. Besides Kv1.3/KCNA3 channels, Anuroctoxin also significantly inhibit Kv1.2/KCNA2 (Kd= 6 nM) channels with an approximately 7-fold lower affinity than Kv1.3/KCNA3 channels[3]. These same experiments showed that Anuroctoxin does not block any of the following channels: calcium-activated KCa3.1/KCNN4 potassium channels, Shaker IR, Kv1.1/KCNA1, and Kv2.1/KCNB1 potassium channels.
Mode of action[edit]
The α-KTx inhibition of the potassium channels is mediated by a simple bimolecular plugging mechanism: the extra cellular pore, which has a specific receptor site, is occluded by the α-KTx binding to it[6][7][8][9]. But whether this block is voltage dependent, which is common in scorpion toxins[10]remains to be seen. This pore block is however fully reversible, which implies that it is not a potent neurotoxin[3]. And the dose–response relationship of the Anuroctoxin on the inhibition of the Kv1.3 channel showed a Hill coefficient of approximately one; which suggest that one peptide interacts with one potassium pore. [3].
References[edit]
- ^ Carbone, E., E. Wanke, G. Prestipino, L. D. Possani, and A. Maelicke (1982). "Selective blockage of voltage-dependent K+ channels by a novel scorpion toxin". Nature. 296(5852): 90–1. PMID 6278313.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Possani. L. D.. B. M. Martin. and I. Svendsen (1982). "The Primar structure of noxiustoxin: A K+ channel blocking peptide, purified from the venom of the scorpion Centruroides noxius Hoffmann". Carlsberg Research Communications. 47: 285–289. doi:10.1007/BF02907789.
- ^ a b c d e f g h Bagdany, M., C. V. Batista; et al. (2005). "Anuroctoxin, a new scorpion toxin of the alpha-KTx 6 subfamily, is highly selective for Kv1.3 over IKCa1 ion channels of human T lymphocytes". Mol Pharmacol. 67 (10): 1034-1044. PMID 15615696.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Tytgat, J., Chandy, K, G., Garcia, M, L., Gutman, G, A., Martin-Eauclaire, M, F., van der Walt, J, J., Possani, L, D (1999). "A unified nomenclature for short-chain peptides isolated from scorpion venoms: alpha-KTx molecular subfamilies". Trends Pharmacol Sci. 20(11): 444–7. PMID 10542442.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Tytgat J, Debont T, Rostoll K, Müller GJ, Verdonck F, Daenens P, van der Walt JJ, Possani LD (1998). "Purification and partial characterization of a 'short' insectotoxin-like peptide from the venom of the scorpion Parabuthus schlechteri". FEBS Lett. 3: 387–91. PMID 9891977.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ MacKinnon, R., and Miller, C. (1988). "Mechanism of charybdotoxin block of Ca"-activated K' channels". J. Gen. Physiol. 97: 335–349. PMID 2454283.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Anderson, C., MacKinnon, R., Smith, C., and Miller, C. (1988). "Charybdotoxin block of single Ca2+-activated K+ channels. Effects of channel gating, voltage, and ionic strength". J. Gen. Physiol. 91: 317–333. PMID 2454282.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Miller, C. (1988). "Competition for block of a Ca*+-activated K'channel by charybdotoxin and tetraethylammonium". Neuron. 1: 1003–1006. PMID 2483092.
- ^ Miller, C. (1992). "Interaction of charybdotoxin with permeant ions inside the pore of a K+ channel". Neuron. 9: 307–313. PMID 1379820.
- ^ Goldstein, S. A. and C. Miller (1993). "Mechanism of charybdotoxin block of a voltage-gated K+ channel". Biophysical journal. 65(4): 1613–1619. PMID 7506068.
Category:Ion channel toxins Category:Neurotoxins Category:Invertebrate toxins