BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Scorpion venom contains diverse peptides with specific ion channel activities.
• Alpha-KTx and gamma-KTx subfamilies are known potassium channel blockers.
• HERG channel dysfunction is implicated in cardiac arrhythmias.

Purpose of the Study:

• To isolate, sequence, and characterize a novel HERG channel blocker from Buthus martensi Karsch venom.
• To investigate the structural basis for the dual K+ channel blocking activity of BmTx3.
• To determine the phylogenetic relationship of BmTx3 within K+ channel toxin families.

Main Methods:

• Isolation and sequencing of a novel toxin from scorpion venom.
• Chemical synthesis and pharmacological characterization of the toxin.
• cDNA and genomic gene cloning and analysis.
• Site-directed mutagenesis to create deletion mutants.
• Phylogenetic tree analysis.

Main Results:

• A novel HERG channel blocker, BmTx3, was identified and characterized.
• BmTx3 is identical to a known A-type K+ channel blocker and belongs to the alpha-KTx subfamily 15.
• BmTx3 is the first alpha-KTx peptide with HERG-blocking activity.
• Structural analysis suggests distinct functional faces for HERG and A-type channel blockade.
• A deletion mutant (BmTx3-Y36P37del) lost A-type channel activity but retained HERG-blocking activity.

Conclusions:

• BmTx3 represents a unique scorpion toxin with dual potassium channel blocking capabilities.
• The study proposes a structural model for BmTx3's distinct channel activities.
• BmTx3's intermediate phylogenetic position highlights evolutionary links between K+ channel toxin subfamilies.