The peptide PnPP-19, a spider toxin derivative, activates ?-opioid receptors and modulates calcium channels

Freitas, Ana C.N.; Peigneur, Steve; Macedo, Fl�vio H.P.; Menezes-Filho, Jos� E.; Millns, Paul; Medeiros, Liciane F.; Arruda, Maria A.; Cruz, Jader; Holliday, Nicholas D.; Tytgat, Jan; Hathway, Gareth; de Lima, Maria E.

Abstract

The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin ?-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, ? and ? opioid receptors. Since the peripheral and central antinociception induced by PnPP-19 involves opioid activation, the aim of this work was to identify whether this synthetic peptide could directly activate opioid receptors and investigate the subtype selectivity for ?-, ?- and/or ?-opioid receptors. Furthermore, we also studied the modulation of calcium influx driven by PnPP-19 in dorsal root ganglion neurons, and analyzed whether this modulation was opioid-mediated. PnPP-19 selectively activates ?-opioid receptors inducing indirectly inhibition of calcium channels and hereby impairing calcium influx in dorsal root ganglion (DRG) neurons. Interestingly, notwithstanding the activation of opioid receptors, PnPP-19 does not induce ?-arrestin2 recruitment. PnPP-19 is the first spider toxin derivative that, among opioid receptors, selectively activates ?-opioid receptors. The lack of ?-arrestin2 recruitment highlights its potential for the design of new improved opioid agonists.

Citation

Freitas, A. C., Peigneur, S., Macedo, F. H., Menezes-Filho, J. E., Millns, P., Medeiros, L. F., …de Lima, M. E. (2018). The peptide PnPP-19, a spider toxin derivative, activates μ-opioid receptors and modulates calcium channels. Toxins, 10(1), 1-12. https://doi.org/10.3390/toxins10010043

• Journal Article Type: Article
• Acceptance Date: Jan 12, 2018
• Online Publication Date: Jan 15, 2018
• Publication Date: Jan 15, 2018
• Deposit Date: May 27, 2020
• Publicly Available Date: May 27, 2020
• Journal: Toxins
• Electronic ISSN: 2072-6651
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 1
• Article Number: 43
• Pages: 1-12
• DOI: https://doi.org/10.3390/toxins10010043
• Public URL: https://nottingham-repository.worktribe.com/output/3112148
• Publisher URL: https://www.mdpi.com/2072-6651/10/1/43