Scorpion toxin peptide action at the ion channel subunit level

Abstract

a b s t r a c tThis review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes. The identification and functional characterisation of these SCTX peptides has tremendous potential for development of novel pharmaceuticals that advance knowledge of ion channels and establish lead compounds for treatment of excitable tissue disorders. This review delineates the unique specificities of 320 individual SCTX peptides that collectively act on 41 ion channel subclasses. Thus the SCTX research field has significant translational implications for pathophysiology spanning neurotransmission, neurohumoral signalling, sensori-motor systems and excitation-contraction coupling.This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'

Australian Scorpion Hormurus waigiensis Venom Fractions Show Broad Bioactivity through Modulation of Bio-Impedance and Cytosolic Calcium

“…The GCaMP5G-RyR1-HEK293 bioreporter cell line had enhanced sensitivity for Ca 2+ mobilization. While it was not possible to specifically delineate scorpion venom-mediated positive modulation of RyR channels, such action has previously been reported with calcin-like molecules isolated from several scorpion venoms [26]. In support of this, the temporal response for Ca 2+ increases quickly in the present study (commencing within 30 sec of venom application and developing over 5-10 min), which closely matches data reported for the calcin imperacalcin (IpTxa; 3.7 kDa), when applied at 20 nM within a sarcoplasmic reticulum heavy vesicle model using the Ca 2+ reporter Arsenazio III [41].…”

“…This makes the increase in cytosolic Ca 2+ elicited here by many of the H. waigiensis venom components likely to have arisen from intracellular Ca 2+ store release. There is also a distinct possibility that H. waigiensis venom components, as for peptides in other scorpion species, also modulate Na + and K + channels, typically leading to membrane depolarization (for reviews [1,26,40]) and driving secondary activation of Cav channels. Given the complexity of the xCELLigence impedance responses, second and third order channel activation could contribute to the observed venom activity.…”

“…This mirrors the typical relative abundance of toxin components against K + and Na + channels (for example~38% each in the red Indian scorpion Mesobuthus tamulus, compared to 0.8% for a Ca 2+ channel toxin [3]). Identification of SCTXs with actions on Ca 2+ entry channels and Ca 2+ store release would offer significant potential for development of therapeutic agents and molecular carriers [25][26][27] and it is unclear what the breadth of impact on Ca 2+ mobilization is across the highly diverse molecular mosaic of scorpion venoms.…”

Antivenom Evaluation by Electrophysiological Analysis

“…Among the molecular mechanisms of venom activity, the impairment of proper cell communication—mainly between muscle and nerve tissue or nerve terminals and secretory glands—is best-defined [17,18]. Various types of receptors, including ion channels, are the main targets of the deleterious components found in animal venoms, and their functional alterations induced by the venom are well characterized and defined by electrophysiological experiments [19,20,21,22]. Major advances in the field of toxin-binding studies have been facilitated by the availability of many cloned genes coding for human ion-channels.…”

Targeting Acid-Sensing Ion Channels by Peptide Toxins

“…With great interests in venom toxins, scientists are extremely involved and enthusiastic about this area of research, as applications of these venoms for drugs could bring about a greater understanding of human diseases, potentially changing and advancing human healthcare [61,65]. Venoms of species like spiders, sea anemones and snakes have been found to target ion channels with highly therapeutic potentials as drug candidates [17,38]. To explore structure-function, gating mechanisms and tissue localization of many ion channels, animal venom toxins were important pharmacological tools in the ion channel field [28].…”