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Centipede Toxins Acting on the Nervous System: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Yalan Han.

Centipedes are typical venomous arthropods that rely on their toxins primarily for predation and defense. Venoms are a complex cocktail of biologically active molecules, including peptides, proteins, polyamide, and enzymes widely produced by venomous organisms. Through long-term evolution, venomous animals have evolved highly specific and diversified peptides and proteins targeting key physiological elements, including the nervous system.

  • venom
  • centipede
  • peptide
  • protein

1. Introduction

Centipedes are excellent predatory arthropods. They deploy a broad set of bioactive peptides to capture prey or defend against predators [23,38,47,48,49,50][1][2][3][4][5][6]. Neurotoxins are the primary predation and defense peptides in centipede venom and also important ingredients that have made significant progress in revealing the biological activities and action mechanisms in recent research. These components act on a wide array of targets, mostly the ion channels, either by activating or inhibiting their electric activity.

2. Toxins Targeting Voltage-Gated Sodium Channels

Voltage-gated sodium channels (NaV) are critical molecular determinants of electrical impulses (action potentials) initiation and propagation, which underlie the electrical hyperexcitability characteristic of chronic inflammatory and neuropathic pain [51,52][7][8]. In-depth research has been made on the venom of the Chinese red-head centipede, Scolopendra subspinipes mutilans L. Koch. μ-SLPTX-Ssm1a was a selective TTX-sensitive (TTX-S) NaV channel inhibitor with the complete amino acid sequence ADNKFENSLRREIACGQCRDKVKCDPYFYHCG [12][9]. Interestingly, another selective NaV channel inhibitor with an almost identical N-terminal sequence of μ-SLPTX-Ssm1a was further discovered from the S. subspinipes mutilans. μ-SLPTX-Ssm6a consists of 46 amino acid residues, yielding a molecular mass of 5318.4 Da. By using whole-cell patch-clamp recordings, this peptide potently inhibited the NaV1.7 channel with a half-maximal inhibitory concentration (IC50) of ~25 nM, which showed a much higher selective than other human sodium channels subtypes (Figure 1). In addition, μ-SLPTX-Ssm6a exhibited an analgesic effect than morphine in formalin-induced pain models. Moreover, μ-SLPTX-Ssm6a showed an almost equal analgesic effect with morphine in thermal and acid-related pain models [21][10]. Many neurotoxins from venomous animals such as scorpion, spider and snail also target NaV1.7. For instance, ProTx-II, a tarantula toxin, selectively targets the NaV1.7 channel, yielding an IC50 of 0.3 nM [53][11]. Similar to the effect of μ-SLPTX-Ssm6a on rat DRG neurons, ProTx-II shifted the conductance–voltage relationship in a depolarizing direction [53][11] despite their different structures. μ-SLPTX-Ssm6a is composed of three α helix structures, while ProTx-I contains two anti-parallel β-folds, which belong to the inhibitory cystine knot family [54][12].
Figure 1. Representative centipede toxins and related ion channel.
By the venomic and transcriptomic analysis of centipede Scolopendra subspinipes dehaani, Liu et al., identified only one group of peptides with five members coding for an identical mature peptide [22][13]. The Mexican centipede Scolopendra viridis crude venom was also reported to weakly inhibit hNaV1.2 and hNaV1.6 channel subtypes, indicating the existence of sodium channel inhibitors in S. viridis [55][14]. With the help of peptidomics combined with the cDNA library, researchers uncovered another precursor that has activity on the sodium channel [56][15].

3. Toxins Targeting Voltage-Gated Potassium Channels

Voltage-gated potassium channels (KV) distinctively modulate firing action potentials with the NaV channel. The NaV channel depolarizes the membrane potential while the KV channel repolarizes the membrane potential. The KV modulators account for a considerable portion in centipede venom. For instance, 10 families of KV inhibitors were identified from the S. subspinipes dehaani [22][13]. Moreover, the selectivity and potency of KV modulators are variable. SSD559, the most potent KV inhibitor, dose-dependently inhibits potassium channels in DRG neurons, and the IC50 for potassium channel inhibition was 10 nM [22][13]. In contrast, κ-SLPTX-Ssm3a was a weaker KV inhibitor. Application of 200 nM κ-SLPTX-Ssm3a on KV channels of dorsal root ganglion (DRG) neurons inhibits 25 ± 5% currents, and κ-SLPTX-Ssm3a does not entirely diminish the potassium peak currents even up to 5 µM, indicating that κ-SLPTX-Ssm3a is a weak inhibitor of potassium channel [12][9].
Based on centipede toxicity tracking, researchers isolated Ssm spooky toxin, SsTx, from the S. subspinipes mutilans. The structure of SsTx is polarized, with basic amino acids of arginine (position 12) and lysine (position 13) forming a positively charged surface. Further analyses showed that SsTx potently inhibited the KCNQ family with R12 and K13 on SsTx, and formed two pairs of salt bonds with residues 288 (aspartic acid) and 266 (aspartic acid) on KCNQ4, respectively (Figure 1). In addition, SsTx potently disrupts the cardiovascular, nervous, respiratory and muscular systems in rodent and mammal models [15][16]. In a further study, researchers showed that SsTx also inhibits the KV1.3 channel, amplifying the broad-spectrum destructive effect by inhibiting the KCNQ family, and shows that SsTx plays a key role in centipede defense and predation [57][17]. Yajamana et al. reported that SsTx, alone with three identified peptides (SsdTx1-3), could also inhibit the pore of the human Kir6.2 channel [58][18]. Another analog of SsTx, SsTx-4, effectively inhibits Kir1.1, Kir4.1, and Kir6.2/SUR1 channels, which are candidate targets for treating hypertension, depression, and diabetes, respectively [23][1]. Similar peptides were also discovered from other venomous species, including cone snails. κ-, κA-, κM- and I- superfamilies of conotoxins were reported to inhibit KV channels by interacting with the voltage-sensing or pore domains [59][19]. In comparison, most of the KV channel modulators from the centipede venoms target the pore region.

4. Toxins Targeting Voltage-Gated Calcium Channels

Both activators and inhibitors of the CaV channel have been discovered in centipede venoms. Researchers found that ω-SLPTX-Ssm1a potently activated voltage-gated calcium channel (CaV) in rat DRG neurons. Functionally, 10 µM ω-SLPTX-Ssm1a increased the calcium channel currents by ~120%, while ω-SLPTX-Ssm2a inhibits calcium channels in a dose-dependent manner. Functionally, 500 nM and 2.5 μM ω-SLPTX-Ssm2a inhibited the calcium channel current’s amplitude by 45% and 80%, respectively, yielding an IC50 of about 1590 nM [12][9]. SSD1052, a calcium channel inhibitor, was isolated from S. subspinipes dehaani crude venom. Ten nanometers of SSD1052 reversibly blocks the CaV current amplitude by 8.6% [22][13]. To date, most CaV modulators from centipedes are antagonists, and ω-SLPTX-Ssm1a is the only agonist. These peptides are structurally diverse with variable disulfide bonds, and all possess similar molecular mass (about 6 kDa). CaV modulators from other venomous animals, such as cone snails, have been extensively studied. Representative conotoxins, ω-GVIA and ω-MVIIA, potently inhibit N-type calcium channels. ω-MVIIA has been approved by the U.S. Food and Drug Administration to treat chronic pain. Thus, further detailed investigation of the pharmacological properties of centipede venoms is essential.

5. Toxins Targeting TRPV1 Channel

As exhibited earlier, centipede toxins are rich in neurotoxins. The Transient Receptor Potential Vanilloid 1 (TRPV1) channel mediates the heat and pain sensation in the periphery nervous system [60][20]. Yang et al. reported the discovery of a compact toxin from S. subspinipes mutilans. The gene encoding this toxin translated into a 69 aa, which yielded a toxin with 27 amino acids after post-translation modification. RhTx binds tightly to the charge-rich outer pore region of TRPV1 to induce severe pain and provides crucial structural information on the channel’s heat activation machinery (Figure 1) [24][21]. In addition, RhTx was used as a probe to investigate the heat-induced desensitization mechanism of the TRPV1 channel [61][22]. RhTx2 is an analog of RhTx with four more amino acids at the N-terminal. Functionally, RhTx2 desensitized the TRPV1 channel upon application to the extracellular domain, indicating that RhTx2 is also a good tool for the investigation of TRPV1 desensitization and a promising candidate for the development of new analgesics [25][23].

References

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