Abstract
Scorpion toxins represent a variety of tools to explore molecular mechanisms and cellular signaling pathways of many biological functions. These toxins are also promising lead compounds for developing treatments for many neurological diseases. In the current study, we purified a new scorpion toxin designated as BmK NSPK (Buthus martensii Karsch neurite-stimulating peptide targeting Kv channels) from the BmK venom. The primary structure was determined using Edman degradation. BmK NSPK directly inhibited outward K+ current without affecting sodium channel activities, depolarized membrane, and increased spontaneous calcium oscillation in spinal cord neurons (SCNs) at low nanomolar concentrations. BmK NSPK produced a nonmonotonic increase on the neurite extension that peaked at ~10 nM. Mechanistic studies demonstrated that BmK NSPK increased the release of nerve growth factor (NGF). The tyrosine kinases A (TrkA) receptor inhibitor, GW 441756, eliminated the BmK NSPK-induced neurite outgrowth. BmK NSPK also increased phosphorylation levels of protein kinase B (Akt) that is the downstream regulator of TrkA receptors. These data demonstrate that BmK NSPK is a new voltage-gated potassium (Kv) channel inhibitor that augments neurite extension via NGF/TrkA signaling pathway. Kv channels may represent molecular targets to modulate SCN development and regeneration and to develop the treatments for spinal cord injury.
Highlights
Scorpion venoms are the biological weapon for scorpion to capture their prey and defend against their predators
electrospray ionization (ESI)-MS gave the multiple ion charges of 1321.7, 991.6, and 793.5 m/z that corresponded to [M+3H]3+, [M+4H]4+, and [M+5H]5+, respectively, demonstrating that the molecular weight of Buthus martensii Karsch (BmK) neurite-stimulating peptide targeting Kv channels (NSPK) was 3962.3 Da, which is distinct from the molecular weights of currently reported BmK toxins (Figure 1C)
We demonstrated that BmK NSPK increased the spontaneous calcium oscillation (SCO) frequency and amplitude and depolarized membrane with low apparent nanomolar affinity in spinal cord neurons (SCNs) cultures, consistent with its high affinity on the outward potassium channels
Summary
Scorpion venoms are the biological weapon for scorpion to capture their prey and defend against their predators. Studies have demonstrated that scorpion toxins can modulate the gating kinetics of many ion channels, including voltage-gated potassium channels (Kv channels) [8], voltage-gated sodium channels (VGSCs) [7,9], voltage-gated calcium channels (Cav channels) [10], chloride channels [11], and ryanodine receptors [12]. Due to their high affinity and selectivity, scorpion toxins are widely used as tools to explore the gating mechanism of ion channels [13] and their downstream cellular signaling pathways [14]. All scorpion Kv channel inhibitors form a common cysteine-stabilized α-helix-β-sheet (Csαβ) motif [15]
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