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Toxins 2018, 10(1), 43; https://doi.org/10.3390/toxins10010043

The Peptide PnPP-19, a Spider Toxin Derivative, Activates μ-Opioid Receptors and Modulates Calcium Channels

1
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
2
Toxicology and Pharmacology, KU Leuven, 3000 Leuven, Belgium
3
Arthritis Research UK Pain Centre, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
4
Cell Signaling Research Group, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
5
Farmanguinhos, Fiocruz, Brazilian Ministry of Health, Rio de Janeiro 22775-903, Brazil
*
Author to whom correspondence should be addressed.
Received: 22 December 2017 / Revised: 11 January 2018 / Accepted: 12 January 2018 / Published: 15 January 2018
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Abstract

The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-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, μ and δ 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 μ-, δ- and/or κ-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 μ-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 β-arrestin2 recruitment. PnPP-19 is the first spider toxin derivative that, among opioid receptors, selectively activates μ-opioid receptors. The lack of β-arrestin2 recruitment highlights its potential for the design of new improved opioid agonists. View Full-Text
Keywords: Phoneutria nigriventer; opioid receptor; spider toxin; antinociception Phoneutria nigriventer; opioid receptor; spider toxin; antinociception
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Freitas, A.C.N.; Peigneur, S.; Macedo, F.H.P.; Menezes-Filho, J.E.; Millns, P.; Medeiros, L.F.; Arruda, M.A.; Cruz, J.; Holliday, N.D.; Tytgat, J.; Hathway, G.; de Lima, M.E. The Peptide PnPP-19, a Spider Toxin Derivative, Activates μ-Opioid Receptors and Modulates Calcium Channels. Toxins 2018, 10, 43.

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