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A novel family of insect-selective peptide neurotoxins targeting insect large-conductance calcium-activated K+ channels isolated from the venom of the theraphosid spider Eucratoscelus constrictus.
Mol Pharmacol. 2011 Jul; 80(1):1-13.MP

Abstract

Spider venoms are actively being investigated as sources of novel insecticidal agents for biopesticide engineering. After screening 37 theraphosid spider venoms, a family of three new "short-loop" inhibitory cystine knot insecticidal toxins (κ-TRTX-Ec2a, κ-TRTX-Ec2b, and κ-TRTX-Ec2c) were isolated and characterized from the venom of the African tarantula Eucratoscelus constrictus. Whole-cell patch-clamp recordings from cockroach dorsal unpaired median neurons revealed that, despite significant sequence homology with other theraphosid toxins, these 29-residue peptides lacked activity on insect voltage-activated sodium and calcium channels. It is noteworthy that κ-TRTX-Ec2 toxins were all found to be high-affinity blockers of insect large-conductance calcium-activated K(+) (BK(Ca)) channel currents with IC(50) values of 3 to 25 nM. In addition, κ-TRTX-Ec2a caused the inhibition of insect delayed-rectifier K(+) currents, but only at significantly higher concentrations. κ-TRTX-Ec2a and κ-TRTX-Ec2b demonstrated insect-selective effects, whereas the homologous κ-TRTX-Ec2c also resulted in neurotoxic signs in mice when injected intracerebroventricularly. Unlike other theraphosid toxins, κ-TRTX-Ec2 toxins induce a voltage-independent channel block, and therefore, we propose that these toxins interact with the turret and/or loop region of the external entrance to the channel and do not project deeply into the pore of the channel. Furthermore, κ-TRTX-Ec2a and κ-TRTX-Ec2b differ from other theraphotoxins at the C terminus and positions 5 to 6, suggesting that these regions of the peptide contribute to the phyla selectivity and are involved in targeting BK(Ca) channels. This study therefore establishes these toxins as tools for studying the role of BK(Ca) channels in insects and lead compounds for the development of novel insecticides.

Authors+Show Affiliations

School of Medical and Molecular Biosciences, University of Technology, Sydney, PO Box 123, Broadway NSW 2007, Australia. graham.nicholson@uts.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21447641

Citation

Windley, Monique J., et al. "A Novel Family of Insect-selective Peptide Neurotoxins Targeting Insect Large-conductance Calcium-activated K+ Channels Isolated From the Venom of the Theraphosid Spider Eucratoscelus Constrictus." Molecular Pharmacology, vol. 80, no. 1, 2011, pp. 1-13.
Windley MJ, Escoubas P, Valenzuela SM, et al. A novel family of insect-selective peptide neurotoxins targeting insect large-conductance calcium-activated K+ channels isolated from the venom of the theraphosid spider Eucratoscelus constrictus. Mol Pharmacol. 2011;80(1):1-13.
Windley, M. J., Escoubas, P., Valenzuela, S. M., & Nicholson, G. M. (2011). A novel family of insect-selective peptide neurotoxins targeting insect large-conductance calcium-activated K+ channels isolated from the venom of the theraphosid spider Eucratoscelus constrictus. Molecular Pharmacology, 80(1), 1-13. https://doi.org/10.1124/mol.110.070540
Windley MJ, et al. A Novel Family of Insect-selective Peptide Neurotoxins Targeting Insect Large-conductance Calcium-activated K+ Channels Isolated From the Venom of the Theraphosid Spider Eucratoscelus Constrictus. Mol Pharmacol. 2011;80(1):1-13. PubMed PMID: 21447641.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel family of insect-selective peptide neurotoxins targeting insect large-conductance calcium-activated K+ channels isolated from the venom of the theraphosid spider Eucratoscelus constrictus. AU - Windley,Monique J, AU - Escoubas,Pierre, AU - Valenzuela,Stella M, AU - Nicholson,Graham M, Y1 - 2011/03/29/ PY - 2011/3/31/entrez PY - 2011/3/31/pubmed PY - 2011/9/17/medline SP - 1 EP - 13 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 80 IS - 1 N2 - Spider venoms are actively being investigated as sources of novel insecticidal agents for biopesticide engineering. After screening 37 theraphosid spider venoms, a family of three new "short-loop" inhibitory cystine knot insecticidal toxins (κ-TRTX-Ec2a, κ-TRTX-Ec2b, and κ-TRTX-Ec2c) were isolated and characterized from the venom of the African tarantula Eucratoscelus constrictus. Whole-cell patch-clamp recordings from cockroach dorsal unpaired median neurons revealed that, despite significant sequence homology with other theraphosid toxins, these 29-residue peptides lacked activity on insect voltage-activated sodium and calcium channels. It is noteworthy that κ-TRTX-Ec2 toxins were all found to be high-affinity blockers of insect large-conductance calcium-activated K(+) (BK(Ca)) channel currents with IC(50) values of 3 to 25 nM. In addition, κ-TRTX-Ec2a caused the inhibition of insect delayed-rectifier K(+) currents, but only at significantly higher concentrations. κ-TRTX-Ec2a and κ-TRTX-Ec2b demonstrated insect-selective effects, whereas the homologous κ-TRTX-Ec2c also resulted in neurotoxic signs in mice when injected intracerebroventricularly. Unlike other theraphosid toxins, κ-TRTX-Ec2 toxins induce a voltage-independent channel block, and therefore, we propose that these toxins interact with the turret and/or loop region of the external entrance to the channel and do not project deeply into the pore of the channel. Furthermore, κ-TRTX-Ec2a and κ-TRTX-Ec2b differ from other theraphotoxins at the C terminus and positions 5 to 6, suggesting that these regions of the peptide contribute to the phyla selectivity and are involved in targeting BK(Ca) channels. This study therefore establishes these toxins as tools for studying the role of BK(Ca) channels in insects and lead compounds for the development of novel insecticides. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/21447641/A_novel_family_of_insect_selective_peptide_neurotoxins_targeting_insect_large_conductance_calcium_activated_K+_channels_isolated_from_the_venom_of_the_theraphosid_spider_Eucratoscelus_constrictus_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21447641 DB - PRIME DP - Unbound Medicine ER -