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|Title:||Assignment of voltage-gated potassium channel blocking activity to κ-KTx1.3, a non-toxic homologue of κ-hefutoxin-1, from Heterometrus spinifer venom||Authors:||Nirthanan, S.
Voltage-gated potassium channel
|Issue Date:||2005||Citation:||Nirthanan, S., Pil, J., Abdel-Mottaleb, Y., Tytgat, J., Sugahara, Y., Sato, K., Gopalakrishnakone, P., Joseph, J.S. (2005). Assignment of voltage-gated potassium channel blocking activity to κ-KTx1.3, a non-toxic homologue of κ-hefutoxin-1, from Heterometrus spinifer venom. Biochemical Pharmacology 69 (4) : 669-678. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bcp.2004.10.018||Abstract:||A new family of weak K+ channel toxins (designated κ-KTx) with a novel "bi-helical" scaffold has recently been characterized from Heterometrus fulvipes (Scorpionidae) venom. Based on the presence of the minimum functional dyad (Y5 and K19), κ-hefutoxin-1 (κ-KTx1.1) was investigated and found to block Kv 1.2 (IC50 ∼40 μM) and Kv 1.3 (IC50 ∼150 μM) channels. In the present study, κ-KTx1.3, that shares ∼60% identity with κ-hefutoxin 1, has been isolated from Heterometrus spinifer venom. Interestingly, despite the presence of the functional dyad (Y5 and K19), κ-KTx1.3 failed to reproduce the K+ channel blocking activity of κ-hefutoxin-1. Since the dyad lysine in κ-KTx1.3 was flanked by another lysine (K20), it was hypothesized that this additional positive charge could hinder the critical electrostatic interactions known to occur between the dyad lysine and the Kv 1 channel selectivity filter. Hence, mutants of κ-KTx1.3, substituting K20 with a neutral (K20A) or a negatively (K20E) or another positively (K20R) charged amino acid were synthesized. κ-KTx1.3 K20E, in congruence with κ-hefutoxin 1 with respect to subtype selectivity and affinity, produced blockade of Kv 1.2 (IC50 = 36.8 ± 4.9 μM) and Kv 1.3 (IC50 = 53.7 ± 6.7 μM) but not Kv 1.1 channels. κ-KTx1.3 K20A produced blockade of both Kv 1.2 (IC50 = 36.9 ± 4.9 μM) and Kv 1.3 (IC50 = 115.7 ± 7.3 μM) and in addition, acquired affinity for Kv 1.1 channels (IC50 = 110.7 ± 7.7 μM). κ-KTx1.3 K20R failed to produce any blockade on the channel subtypes tested. These data suggest that the presence of an additional charged residue in a position adjacent to the dyad lysine impedes the functional block of Kv 1 channels produced by κ-KTx1.3. © 2004 Elsevier Inc. All rights reserved.||Source Title:||Biochemical Pharmacology||URI:||http://scholarbank.nus.edu.sg/handle/10635/33748||ISSN:||00062952||DOI:||10.1016/j.bcp.2004.10.018|
|Appears in Collections:||Staff Publications|
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