Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

Diochot, Sylvie

doi:10.1590/1678-9199-JVATITD-2021-0026

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Journal of Venomous Animals and Toxins including Tropical Diseases

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REVIEW • J. Venom. Anim. Toxins incl. Trop. Dis 27 • 2021 • https://doi.org/10.1590/1678-9199-JVATITD-2021-0026 copy

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Pain is a common symptom induced during envenomation by spiders and scorpions. Toxins isolated from their venom have become essential tools for studying the functioning and physiopathological role of ion channels, as they modulate their activity. In particular, toxins that induce pain relief effects can serve as a molecular basis for the development of future analgesics in humans. This review provides a summary of the different scorpion and spider toxins that directly interact with pain-related ion channels, with inhibitory or stimulatory effects. Some of these toxins were shown to affect pain modalities in different animal models providing information on the role played by these channels in the pain process. The close interaction of certain gating-modifier toxins with membrane phospholipids close to ion channels is examined along with molecular approaches to improve selectivity, affinity or bioavailability in vivo for therapeutic purposes.

Keywords:
Venom; Toxin; Spider; Scorpion; Pain; Ion channels

Scorpion species	Toxin	Action mode	Ion channel	Type of effect	Pain phenotype [references]
Androctonus australis	AaH II	α-toxin	TTX-S Nav (Nav1.7)	Pain	Acute, mechanical and thermal pain (ipl) [123123. Abbas N, Gaudioso-Tyzra C, Bonnet C, Gabriac M, Amsalem M, Lonigro A, Padilla F, Crest M, Martin-Eauclaire MF, Delmas P. The scorpion toxin Amm VIII induces pain hypersensitivity through gain-of-function of TTX-sensitive Na(+) channels. Pain. 2013;154(8):1204-15.]
Androctonus mauretanicus	Amm VIII	α-toxin	TTX-S Nav Nav1.7	Pain	Acute, mechanical and thermal pain (ipl) [123123. Abbas N, Gaudioso-Tyzra C, Bonnet C, Gabriac M, Amsalem M, Lonigro A, Padilla F, Crest M, Martin-Eauclaire MF, Delmas P. The scorpion toxin Amm VIII induces pain hypersensitivity through gain-of-function of TTX-sensitive Na(+) channels. Pain. 2013;154(8):1204-15.]
Androctonus mauretanicus	anatoxin Amm VIII	α-toxin	Nav1.2	Analgesia	Thermal (ip) pain [125125. Martin-Eauclaire MF, Abbas N, Sauze N, Mercier L, Berge-Lefranc JL, Condo J, Bougis PE, Guieu R. Involvement of endogenous opioid system in scorpion toxin-induced antinociception in mice. Neurosci Lett. 2010 Sep 20;482(1):45-50.]
Buthus martensii Karsch	BmK I	α-toxin	Nav1.6 (pot) Nav1.8 (pot)	Pain	Acute, inflammatory thermal pain, mechanical hyperalgesia (ipl) [115115. Chen J, Tan ZY, Zhao R, Feng XH, Shi J, Ji YH. The modulation effects of BmK I, an alpha-like scorpion neurotoxin, on voltage-gated Na(+) currents in rat dorsal root ganglion neurons. Neurosci Lett. 2005;390:66-71.,116116. Bai ZT, Liu T, Jiang F, Cheng M, Pang XY, Hua LM, Shi J, Zhou JJ, Shu XQ, Zhang JW, Ji YH. Phenotypes and peripheral mechanisms underlying inflammatory pain-related behaviors induced by BmK I, a modulator of sodium channels. Exp Neurol. 2010 Aug 22;226(1):159-72.,118118. Qin S, Jiang F, Zhou Y, Zhou G, Ye P, Ji Y. Local knockdown of Nav1.6 relieves pain behaviors induced by BmK I. Acta Biochim Biophys Sin (Shanghai). 2017 Aug;49(8):713-21.-120120. Ye P, Hua L, Jiao Y, Li Z, Qin S, Fu J, Jiang F, Liu T, Ji Y. Functional up-regulation of Nav1.8 sodium channel on dorsal root ganglia neurons contributes to the induction of scorpion sting pain. Acta Biochim Biophys Sin (Shanghai). 2016 Feb;48(2):132-44.]
	BmK IT2	β-toxin	TTX-R &TTX-S Nav (inh)	Analgesia	Acute, inflammatory pain, thermal hyperalgesia (it, ipl) [133133. Wang CY, Tan ZY, Chen B, Zhao ZQ, Ji YH. Antihyperalgesia effect of BmK IT2, a depressant insect-selective scorpion toxin in rat by peripheral administration. Brain Res Bull. 2000 Oct;53(3):335-8.-136136. Tan ZY, Xiao H, Mao X, Wang CY, Zhao ZQ, Ji YH. The inhibitory effects of BmK IT2, a scorpion neurotoxin on rat nociceptive flexion reflex and a possible mechanism for modulating voltage-gated Na(+) channels. Neuropharmacology. 2001 Mar;40(3):352-7.]
	BmK IT-AP	Excitatory insect β-toxin	ND	Analgesia	Visceral pain (iv) [138138. Guan RJ, Wang M, Wang D, Wang DC. A new insect neurotoxin AngP1 with analgesic effect from the scorpion Buthus martensii Karsch: purification and characterization. J Pept Res. 2001 Jul;58(1):27-35.,150150. Xiong YM, Lan ZD, Wang M, Liu B, Liu XQ, Fei H, Xu LG, Xia QC, Wang CG, Wang DC, Chi CW. Molecular characterization of a new excitatory insect neurotoxin with an analgesic effect on mice from the scorpion Buthus martensi Karsch. Toxicon. 1999 Aug;37(8):1165-80.]
	BmK IT AP3	Depressant insect toxin	ND	Analgesia	Visceral pain (iv) [138138. Guan RJ, Wang M, Wang D, Wang DC. A new insect neurotoxin AngP1 with analgesic effect from the scorpion Buthus martensii Karsch: purification and characterization. J Pept Res. 2001 Jul;58(1):27-35.]
	BmK AS BmK AS-1	β-toxin	TTX-R &TTX-S Nav (inh)	Analgesia	Visceral (ip, iv), thermal(iv), Inflammatory (it) pain, mechanical hyperalgesia (ipl) [3232. Chen J, Feng XH, Shi J, Tan ZY, Bai ZT, Liu T, Ji YH. The anti-nociceptive effect of BmK AS, a scorpion active polypeptide, and the possible mechanism on specifically modulating voltage-gated Na+ currents in primary afferent neurons. Peptides. 2006 Sep;27(9):2182-92.,131131. Chen B, Ji Y. Antihyperalgesia effect of BmK AS, a scorpion toxin, in rat by intraplantar injection. Brain Res. 2002 Oct 18;952(2):322-6.,132132. Liu T, Pang XY, Jiang F, Bai ZT, Ji YH. Anti-nociceptive effects induced by intrathecal injection of BmK AS, a polypeptide from the venom of Chinese-scorpion Buthus martensi Karsch, in rat formalin test. J Ethnopharmacol. 2008 May 8;117(2):332-8.]
	BmK AGP-SYPU1&2	α/β-toxin	Nav1.4; Nav1.5; Nav1.7	Analgesia	Visceral (ip, iv) pain [339339. Wang Y, Wang L, Cui Y, Song YB, Liu YF, Zhang R, Wu CF, Zhang JH. Purification, characterization and functional expression of a new peptide with an analgesic effect from Chinese scorpion Buthus martensii Karsch (BmK AGP-SYPU1). Biomed Chromatogr. 2011;25:801-7.]
	BmK AGAP-SYPU1&2	α/β-toxin	ND	Analgesia	Visceral (ip, iv), thermal (iv) pain [340340. Shao JH, Cui Y, Zhao MY, Wu CF, Liu YF, Zhang JH. Purification, characterization, and bioactivity of a new analgesic-antitumor peptide from Chinese scorpion Buthus martensii Karsch. Peptides. 2014 Mar;53:89-96.]
	BmK AGAP	α/β-toxin	Nav1.4, Nav1.5 Nav1.7, Nav1.8 (inh)	Analgesia	Visceral (ip), inflammatory (ipl, iv), thermal (iv) pain [146146. Mao Q, Ruan J, Cai X, Lu W, Ye J, Yang J, Yang Y, Sun X, Cao J, Cao P. Antinociceptive effects of analgesic-antitumor peptide (AGAP), a neurotoxin from the scorpion Buthus martensii Karsch, on formalin-induced inflammatory pain through a mitogen-activated protein kinases-dependent mechanism in mice. PLoS One. 2013 Nov 14;8(11):e78239.,147147. Ma R, Cui Y, Zhou Y, Bao YM, Yang WY, Liu YF, Wu CF, Zhang JH. Location of the analgesic domain in Scorpion toxin BmK AGAP by mutagenesis of disulfide bridges. Biochem Biophys Res Commun. 2010 Apr 2;394(2):330-4.]
	BmK AngM1		Nav (inh)	Analgesia	Visceral pain (iv) [148148. Cao ZY, Mi ZM, Cheng GF, Shen WQ, Xiao X, Liu XM, Liang XT, Yu DQ. Purification and characterization of a new peptide with analgesic effect from the scorpion Buthus martensi Karch. J Pept Res. 2004 Jul;64(1):33-41.]
	BmK AngP1	Excitatory insect toxin	ND	Analgesia	Visceral pain (iv) [138138. Guan RJ, Wang M, Wang D, Wang DC. A new insect neurotoxin AngP1 with analgesic effect from the scorpion Buthus martensii Karsch: purification and characterization. J Pept Res. 2001 Jul;58(1):27-35.]
	ANEP toxin	β-toxin	Nav1.7 (inh)	Analgesia	Visceral pain (iv) [3333. Song Y, Liu Z, Zhang Q, Li C, Jin W, Liu L, Zhang J, Zhang J. Investigation of Binding Modes and Functional Surface of Scorpion Toxins ANEP to Sodium Channels 1.7. Toxins (Basel). 2017 Dec;9(12):387.]
	BmP01		TRPV1 (act) Kv1.3 (inh)	Pain	Acute pain (ipl) [160160. Hakim MA, Jiang W, Luo L, Li B, Yang S, Song Y, Lai R. Scorpion Toxin, BmP01, Induces Pain by Targeting TRPV1 Channel. Toxins (Basel). 2015 Sep 14;7(9):3671-87.,161161. Geron M, Hazan A, Priel A. Animal Toxins Providing Insights into TRPV1 Activation Mechanism. Toxins (Basel). 2017 Oct;9(10):326.]
Buthus occitanus tunetanus	Bot AF	β-like-toxin	ND	Analgesia	Heat (ip, it), inflammatory (ipl), visceral (ip) pain [154154. Maatoug R, Jebali J, Guieu R, De Waard M, Kharrat R. BotAF, a new Buthus occitanus tunetanus scorpion toxin, produces potent analgesia in rodents. Toxicon. 2018 Jul;149:72-85.]
Centruroides elegans	CeII8	β-toxin	Nav1.7 (inh)	ND	[139139. Vandendriessche T, Olamendi-Portugal T, Zamudio FZ, Possani LD, Tytgat J. Isolation and characterization of two novel scorpion toxins: The alpha-toxin-like CeII8, specific for Na(v)1.7 channels and the classical anti-mammalian CeII9, specific for Na(v)1.4 channels. Toxicon. 2010 Sep 15;56(4):613-23.]
Centruroides vittatus	Cv IV4	α-toxin	Nav1.2, Nav1.3, Nav1.4, Nav1.7 (pot)	Pain	Acute pain (ipl) [2121. Rowe AH, Xiao Y, Scales J, Linse KD, Rowe MP, Cummins TR, Zakon HH. Isolation and characterization of CvIV4: a pain inducing alpha-scorpion toxin. PLoS One. 2011;6(8):e23520.]
Centruroides noxius	Cn2	β-toxin	Nav1.6 (act)	Pain	Acute pain, mechanical cold allodynia (ipl) [143143. Israel MR, Tanaka BS, Castro J, Thongyoo P, Robinson SD, Zhao P, Deuis JR, Craik DJ, Durek T, Brierley SM, Waxman SG, Dib-Hajj SD, Vetter I. NaV 1.6 regulates excitability of mechanosensitive sensory neurons. J Physiol. 2019 Jul;597(14):3751-68.,144144. Deuis JR, Zimmermann K, Romanovsky AA, Possani LD, Cabot PJ, Lewis RJ, Vetter I. An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. Pain. 2013 Sep;154(9):1749-57.]
Leiurus quinquestriatus	LqqIT2	Insect β-toxin	ND	Analgesia	Thermal pain (ip) [125125. Martin-Eauclaire MF, Abbas N, Sauze N, Mercier L, Berge-Lefranc JL, Condo J, Bougis PE, Guieu R. Involvement of endogenous opioid system in scorpion toxin-induced antinociception in mice. Neurosci Lett. 2010 Sep 20;482(1):45-50.]
Leiurus quinquestriatus	LqhIII	α-like toxin	Nav1.7 (pot)	ND	[124124. Chen H, Lu S, Leipold E, Gordon D, Hansel A, Heinemann SH. Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3. Eur J Neurosci. 2002 Aug;16(4):767-70.]
Odonthobuthus doriae	OD1	α-like-toxin α/β-toxin	Nav1.7, Nav1.3 Nav1.4, Nav1.6 (pot)	Pain	Acute pain (ipl) [126126. Durek T, Vetter I, Wang CI, Motin L, Knapp O, Adams DJ, Lewis RJ, Alewood PF. Chemical engineering and structural and pharmacological characterization of the alpha-scorpion toxin OD1. ACS Chem Biol. 2013;8(6):1215-22.-129129. Motin L, Durek T, Adams DJ. Modulation of human Nav1.7 channel gating by synthetic alpha-scorpion toxin OD1 and its analogs. Channels (Austin). 2016;10(2):139-47.]
Parabuthus transvaalicus	Kurtoxin	α-toxin	Cav3.1, Cav3.2, Cav2.2 (inh); Nav1.2 (pot)	ND	[155155. Chuang RS, Jaffe H, Cribbs L, Perez-Reyes E, Swartz KJ. Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin. Nat Neurosci. 1998 Dec;1(8):668-74.,156156. Sidach SS, Mintz IM. Kurtoxin, a gating modifier of neuronal high- and low-threshold ca channels. J Neurosci. 2002 Mar 15;22(6):2023-34.]
Tityus fasciolatus	Tf2	β-toxin	Nav1.3 (act)	Pain	Acute pain (ipl) [140140. Camargos TS, Bosmans F, Rego SC, Mourao CB, Schwartz EF. The Scorpion Toxin Tf2 from Tityus fasciolatus Promotes Nav1.3 Opening. PLoS One. 2015 Jun 17;10(6):e0128578.,317317. Agwa AJ, Tran P, Mueller A, Tran HNT, Deuis JR, Israel MR, McMahon KL, Craik DJ, Vetter I, Schroeder CI. Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7. J Biol Chem. 2020 Apr 10;295(15):5067-80.]
Tityus serrulatus	Ts2	α-toxin	Nav1.3, Nav1.6, Nav1.7 (pot)	ND	[142142. Cologna CT, Peigneur S, Rustiguel JK, Nonato MC, Tytgat J, Arantes EC. Investigation of the relationship between the structure and function of Ts2, a neurotoxin from Tityus serrulatus venom. FEBS J. 2012 Apr;279(8):1495-1504.]
	TsNTxP		ND	Analgesia	Acute, heat, inflammatory, neuropathic pain (it) [153153. Rigo FK, Bochi GV, Pereira AL, Adamante G, Ferro PR, Dal-Toe De Pra S, Milioli AM, Damiani AP, da Silveira Prestes G, Dalenogare DP, Chavez-Olortegui C, Moraes de Andrade V, Machado-de-Avila RA, Trevisan G. TsNTxP, a non-toxic protein from Tityus serrulatus scorpion venom, induces antinociceptive effects by suppressing glutamate release in mice. Eur J Pharmacol. 2019 Jul 15;855:65-74.]
	Ts8 (TsK2 or TsTx-Kβ)	β-KTx	Kv4.2 (inh)	Pain	Acute pain mechanical hyperalgesia (ipl, it) [6262. Pucca MB, Cerni FA, Cordeiro FA, Peigneur S, Cunha TM, Tytgat J, Arantes EC. Ts8 scorpion toxin inhibits the Kv4.2 channel and produces nociception in vivo. Toxicon. 2016 Sep 1;119:244-52.]
Urodacus manicatus	WaTx		TRPA1 (act)	Pain	Acute pain (ipl) [163163. Lin King JV, Emrick JJ, Kelly MJS, Herzig V, King GF, Medzihradszky KF, Julius D. A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain. Cell. 2019 Sep 5;178(6):1362-74.e16.]

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[1] *Correspondence: diochot@ipmc.cnrs.fr