Novel Scorpion Toxin ω-Buthitoxin-Hf1a Selectively Inhibits Calcium Influx via CaV3.3 and CaV3.2 and Alleviates Allodynia in a Mouse Model of Acute Postsurgical Pain

被引：0

作者：

Wang, Dan ^{[1
,2
]}

Herzig, Volker ^{[3
,4
]}

Dekan, Zoltan ^{[2
]}

Rosengren, K. Johan ^{[5
]}

Payne, Colton D. ^{[5
]}

Hasan, Md. Mahadhi ^{[6
]}

Zhuang, Jiajie ^{[1
]}

Bourinet, Emmanuel ^{[7
]}

Ragnarsson, Lotten ^{[2
]}

Alewood, Paul F. ^{[2
]}

Lewis, Richard J. ^{[2
]}

机构：

[1] Jiangsu Univ, Sch Pharm, Dept Chinese Med & Pharm, Zhenjiang 212013, Peoples R China

[2] Univ Queensland, Div Chem & Struct Biol, Inst Mol Biosci, Brisbane, Qld 4072, Australia

[3] Univ Sunshine Coast, Ctr Bioinnovat, Sippy Downs, Qld 4556, Australia

[4] Univ Sunshine Coast, Sch Sci Technol & Engn, Sippy Downs, Qld 4556, Australia

[5] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia

[6] Khulna Univ, Life Sci Sch, Pharm Discipline, Khulna 9208, Bangladesh

[7] Montpellier Univ, Inst Funct Genom, CNRS, INSERM, F-34090 Montpellier, France

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2024年 / 25卷 / 09期

基金：

澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

venom peptides; T-type calcium channels; peripheral pain; acute post-surgical pain; T-TYPE; SENSORY NEURONS; CA2+ CHANNELS; SPIDER TOXINS; PEPTIDES; GENE; HYPERALGESIA; NOMENCLATURE; NOCICEPTION; VALIDATION;

D O I：

10.3390/ijms25094745

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Venom peptides have evolved to target a wide range of membrane proteins through diverse mechanisms of action and structures, providing promising therapeutic leads for diseases, including pain, epilepsy, and cancer, as well as unique probes of ion channel structure-function. In this work, a high-throughput FLIPR window current screening assay on T-type Ca(V)3.2 guided the isolation of a novel peptide named omega-Buthitoxin-Hf1a from scorpion Hottentotta franzwerneri crude venom. At only 10 amino acid residues with one disulfide bond, it is not only the smallest venom peptide known to target T-type Ca(V)s but also the smallest structured scorpion venom peptide yet discovered. Synthetic Hf1a peptides were prepared with C-terminal amidation (Hf1a-NH2) or a free C-terminus (Hf1a-OH). Electrophysiological characterization revealed Hf1a-NH2 to be a concentration-dependent partial inhibitor of Ca(V)3.2 (IC50 = 1.18 mu M) and Ca(V)3.3 (IC50 = 0.49 mu M) depolarized currents but was ineffective at Ca(V)3.1. Hf1a-OH did not show activity against any of the three T-type subtypes. Additionally, neither form showed activity against N-type Ca(V)2.2 or L-type calcium channels. The three-dimensional structure of Hf1a-NH2 was determined using NMR spectroscopy and used in docking studies to predict its binding site at Ca(V)3.2 and Ca(V)3.3. As both Ca(V)3.2 and Ca(V)3.3 have been implicated in peripheral pain signaling, the analgesic potential of Hf1a-NH2 was explored in vivo in a mouse model of incision-induced acute post-surgical pain. Consistent with this role, Hf1a-NH2 produced antiallodynia in both mechanical and thermal pain.

引用

页数：18