Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider

Rocio K Finol-Urdaneta; Rebekah Ziegman; Zoltan Dekan; Jeffrey R McArthur; Stewart Heitmann; Karen Luna-Ramirez; Han-Shen Tae; Alexander Mueller; Hana Starobova; Yanni K-Y Chin; Joshua S Wingerd; Eivind A B Undheim; Ben Cristofori-Armstrong; Adam P Hill; Volker Herzig; Glenn F King; Irina Vetter; Lachlan D Rash; David J Adams; Paul F Alewood

doi:10.1073/pnas.2110932119

Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider

Proc Natl Acad Sci U S A. 2022 Feb 1;119(5):e2110932119. doi: 10.1073/pnas.2110932119.

Authors

Rocio K Finol-Urdaneta^{1

2

3}, Rebekah Ziegman⁴, Zoltan Dekan⁴, Jeffrey R McArthur^{5

3}, Stewart Heitmann⁶, Karen Luna-Ramirez^{5

3}, Han-Shen Tae^{5

3}, Alexander Mueller⁴, Hana Starobova⁴, Yanni K-Y Chin^{4

7}, Joshua S Wingerd⁴, Eivind A B Undheim^{7

8

9}, Ben Cristofori-Armstrong^{4

10}, Adam P Hill^{6

11}, Volker Herzig^{4

12}, Glenn F King^{4

13}, Irina Vetter^{4

14}, Lachlan D Rash^{4

10}, David J Adams^{1

3}, Paul F Alewood¹⁵

Affiliations

¹ Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; rfinolu@uow.edu.au djadams@uow.edu.au p.alewood@imb.uq.edu.au.
² Electrophysiology Facility for Cell Phenotyping and Drug Discovery, Wollongong, NSW 2522, Australia.
³ Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
⁴ Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia.
⁵ Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
⁶ Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
⁷ Centre for Advanced Imaging, University of Queensland, St. Lucia, QLD 4072, Australia.
⁸ Centre for Biodiversity Dynamics, Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁹ Centre for Ecology and Evolutionary Synthesis, Department of Bioscience, University of Oslo, 0316 Oslo, Norway.
¹⁰ School of Biomedical Sciences, University of Queensland, St. Lucia, QLD 4072, Australia.
¹¹ St Vincent's Clinical School, University of New South Wales Sydney, Darlinghurst, NSW 2010, Australia.
¹² School of Science, Technology & Engineering and GeneCology Research Centre, University of the Sunshine Coast, Sippy Downs, QLD 4556, Australia.
¹³ Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Queensland, St. Lucia, QLD 4072, Australia.
¹⁴ School of Pharmacy, University of Queensland, Woolloongabba, QLD 4102, Australia.
¹⁵ Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; rfinolu@uow.edu.au djadams@uow.edu.au p.alewood@imb.uq.edu.au.

Abstract

The King Baboon spider, Pelinobius muticus, is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from P. muticus, but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of P. muticus venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including Na_V1.8, K_V2.1, and tetrodotoxin-sensitive Na_V channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.

Keywords: KV2.1; NaV1.8; hyperexcitability; pain; target promiscuity.

Publication types

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

MeSH terms

Action Potentials / drug effects
Animals
Ganglia, Spinal / drug effects
Hyperalgesia / drug therapy
Ion Channels / metabolism
Mice
Nociceptors / drug effects*
Pain / drug therapy
Papio / metabolism*
Peptides / pharmacology*
Spider Venoms / pharmacology*
Spiders / metabolism*
Tetrodotoxin / pharmacology

Substances

Ion Channels
Peptides
Spider Venoms
Tetrodotoxin