Abstract
BackgroundSpecific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors. Through conducting transcriptomic sequencing for the venom gland of Scorpiops pococki from Xizang province of China, this research aims to discover a novel functional gene encoding peptidic blocker of Kv1.3, and identify its function.ResultsWe screened out a new peptide toxin KTX-Sp4 which had 43 amino acids including six cysteine residues. Electrophysiological experiments indicated that recombinant expression products of KTX-Sp4 blocked both endogenous and exogenous Kv1.3 channel concentration-dependently, and exhibited good selectivity on Kv1.3 over Kv1.1, Kv1.2, respectively. Mutation experiments showed that the Kv1 turret region was responsible for the selectivity of KTX-Sp4 peptide on Kv1.3 over Kv1.1.ConclusionsThis work not only provided a novel lead compound for the development of anti autoimmune disease drugs, but also enriched the molecular basis for the interaction between scorpion toxins and potassium channels, serving as an important theoretical basis for designing high selective Kv1.3 peptide inhibitors.
Highlights
Specific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors
A large number of studies have showed that scorpion venom contains many short peptides with 20-80 amino acid residues, which is an important source of kv1.3 channel inhibitors [11]
Whole cell patch-clamp experiments indicated that peptide KTX-Sp4 had potentially selective blocking effect on Kv1.3 over Kv1.1 channel, and the selective recognition of KTX-Sp4 on Kv1.3 over Kv1.1 was determined by four different amino acid residues in the turret region between Kv1.1 and Kv1.3 channels
Summary
Specific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors. Steroids [2] and cyclophosphamides [3] have been widely used to treat autoimmune diseases They often cause side effects, such as reducing the patient’s normal protective immune response and increasing the risk of infection. A large number of studies have showed that scorpion venom contains many short peptides with 20-80 amino acid residues, which is an important source of kv1.3 channel inhibitors [11]. We screened a scorpion toxin KTX-Sp4 gene by transcriptome sequencing from the venom glands of Scorpiops pococki from Xizang province. Whole cell patch-clamp experiments indicated that peptide KTX-Sp4 had potentially selective blocking effect on Kv1.3 over Kv1.1 channel, and the selective recognition of KTX-Sp4 on Kv1.3 over Kv1.1 was determined by four different amino acid residues in the turret region between Kv1.1 and Kv1.3 channels
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