Two Tarantula Peptides Inhibit Activation of Multiple Sodium Channels

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• 作者：Richard E. Middleton ; Vivien A. Warren ; Richard L. Kraus ; Jeremy C. Hwang ; Chou J. Liu ; Ge Dai ; Richard M. Brochu ; Martin G. Kohler ; Ying-Duo Gao ; Victor M. Garsky ; Michael J. Bogusky ; John T. Mehl ; C
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：December 17, 2002
• 年：2002
• 卷：41
• 期：50
• 页码：14734 - 14747
• 全文大小：316K
• 年卷期：v.41,no.50(December 17, 2002)
• ISSN：1520-4995

文摘

Two peptides, ProTx-I and ProTx-II, from the venom of the tarantula Thrixopelma pruriens,have been isolated and characterized. These peptides were purified on the basis of their ability to reversiblyinhibit the tetrodotoxin-resistant Na channel, Na_V 1.8, and are shown to belong to the inhibitory cystineknot (ICK) family of peptide toxins interacting with voltage-gated ion channels. The family has severalhallmarks: cystine bridge connectivity, mechanism of channel inhibition, and promiscuity across channelswithin and across channel families. The cystine bridge connectivity of ProTx-II is very similar to that ofother members of this family, i.e., C₂ to C₁₆, C₉ to C₂₁, and C₁₅ to C₂₅. These peptides are the first high-affinity ligands for tetrodotoxin-resistant peripheral nerve Na_V channels, but also inhibit other Na_V channels(IC₅₀'s < 100 nM). ProTx-I and ProTx-II shift the voltage dependence of activation of Na_V 1.5 to morepositive voltages, similar to other gating-modifier ICK family members. ProTx-I also shifts the voltagedependence of activation of Ca_V 3.1 (mages/gifchars/alpha.gif" BORDER=0>_1G, T-type, IC₅₀ = 50 nM) without affecting the voltage dependenceof inactivation. To enable further structural and functional studies, synthetic ProTx-II was made; it adoptsthe same structure and has the same functional properties as the native peptide. Synthetic ProTx-I wasalso made and exhibits the same potency as the native peptide. Synthetic ProTx-I, but not ProTx-II, alsoinhibits K_V 2.1 channels with 10-fold less potency than its potency on Na_V channels. These peptidesrepresent novel tools for exploring the gating mechanisms of several Na_V and Ca_V channels.