Toxin Cll1 is a toxin from the venom of the Mexican scorpion Centruroides limpidus limpidus, which changes the activation threshold of sodium channels by binding to neurotoxin binding site 4, resulting in increased excitability.
The toxin Cll1 is named after its producing species, Centruroides limpidus limpidus. Along with Cll1, multiple toxins are excreted in its venom. [2]
Cll1 is a long chain neuropeptide belonging to the scorpion toxin superfamily. Cll1 is classified as a member of the beta-toxin subfamily. [3] The global secondary structure of Cll1 is similar to that of other scorpion beta-toxins, including the alpha-helix, triple stranded antiparallel beta-sheet, and the four disulfide bridges. [4] [5] The higher affinity for crustacean rather than mammalian sodium channels has been attributed to the presence of Trp18, a hydrophobic amino acid at the surface of Cll1. [4]
Cll1 targets, like the classical scorpion beta-toxin, the voltage-gated sodium channels (Nav). Beta-toxins bind to the extracellular end of the voltage sensor S4 at the loop between the 3rd and 4th segment of the second domain. [6] By binding it alters the voltage dependent opening of the channel. [7]
Cll1 influences three intrinsic properties of the targeted sodium channel:
Cll1 binds to transmembrane segment S4 of the voltage gated sodium channels. Its binding shifts the activation threshold of the sodium channel towards more negative membrane potentials. [7] Seven different isoforms of the voltage gated sodium channels (Nav1.1-Nav1.7) have been studied in the presence of Cll1. In almost all of these seven isoforms, Cll1 affects voltage dependent activation. It has only a minor effect on the Nav1.1-1.4 and Nav1.7 channels, but a much larger effect on isoform Nav1.6. [7]
Cll1 causes a reduction of the peak current when bound to the voltage activated sodium channels. This effect was present in all but one of the seven tested isoforms (Nav1.1-Nav1.6). The only isoform that showed no reduction in peak current was Nav1.7. [7]
Cll1 can induce resurgent currents. This effect has also been demonstrated for other beta-scorpion toxins. The resurgent current is strongest in Nav1.6, but it is also present to a much lesser extent in other isoforms of the voltage activated sodium channels. [7]
The LD50 of the Cll1 toxin in mice is 85 μg/kg. [8] A possible treatment for an intoxication by Cll1 toxin is the use of single chain variable fragments (scFv). [8] Other possible treatments find their origin in traditional Mexican medicine. Several herbs used in traditional Mexican medicine have been proven to be effective in treating an intoxication from the whole venom from C. limpidus limpidus in mice, including Bouvardia ternifolia . [9]
Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, voltage-gated sodium channels, voltage-gated potassium channels, and Transient Receptor Potential (TRP) channels. The result of this action is to activate or inhibit the action of these channels in the nervous and cardiac organ systems. For instance, α-scorpion toxins MeuNaTxα-12 and MeuNaTxα-13 from Mesobuthus eupeus are neurotoxins that target voltage-gated Na+ channels (Navs), inhibiting fast inactivation. In vivo assays of MeuNaTxα-12 and MeuNaTxα-13 effects on mammalian and insect Navs show differential potency. These recombinants exhibit their preferential affinity for mammalian and insect Na+ channels at the α-like toxins' active site, site 3, in order to inactivate the cell membrane depolarization faster[6]. The varying sensitivity of different Navs to MeuNaTxα-12 and MeuNaTxα-13 may be dependent on the substitution of a conserved Valine residue for a Phenylalanine residue at position 1630 of the LD4:S3-S4 subunit or due to various changes in residues in the LD4:S5-S6 subunit of the Navs. Ultimately, these actions can serve the purpose of warding off predators by causing pain or to subdue predators.
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