Neurotoxicity of  Tityus bahiensis  (brown scorpion) venom in sympathetic vas deferens preparations and neuronal cells

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Abstract

Systemic scorpion envenomation is characterized by massive neurotransmitter release from peripheral nerves mediated primarily by scorpion venoms neurotoxins. Tityus bahiensis is one of the medically most important species in Brazil, but its venom pharmacology, especially regarding to peripheral nervous system, is poorly understood. Here, we evaluated the T. bahiensis venom activity on autonomic (sympathetic) neurotransmission by using a variety of approaches, including vas deferens twitch-tension recordings, electrophysiological measurements (resting membrane potentials, spontaneous excitatory junctional potentials and whole-cell patch-clamp), calcium imaging and histomorphological analysis. Low concentrations of venom (≤ 3 μg/mL) facilitated the electrically stimulated vas deferens contractions without affecting postsynaptic receptors or damaging the smooth muscle cells. Transient TTX-sensitive sustained contractions and resting membrane depolarization were mediated mainly by massive spontaneous ATP release. High venom concentrations (≥ 10 μg/mL) blocked the muscle contractions and induced membrane depolarization. In neuronal cells (ND7-23 wt), the venom increased the peak sodium current, modified the current-voltage relationship by left-shifting the Na _v-channel activation curve, thereby facilitating the opening of these channels. The venom also caused a time-dependent increase in neuronal calcium influx. These results indicate that the sympathetic hyperstimulation observed in systemic envenomation is presynaptically driven, probably through the interaction of α- and β-toxins with neuronal sodium channels.

Article Highlights

Tityus bahiensis scorpion venom modulates neurotransmission in mouse vas deferens
Facilitation at low venom concentrations involves a presynaptic action
The venom mobilizes intracellular calcium in neurons without causing tissue damage
Sodium channel modulation by venom toxins accounts for most of these effects

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Most cited references 32

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Scorpion toxins specific for Na+-channels

Lourival Possani, Baltazar Becerril, Muriel Delepierre … (1999)

Na+-channel specific scorpion toxins are peptides of 60-76 amino acid residues in length, tightly bound by four disulfide bridges. The complete amino acid sequence of 85 distinct peptides are presently known. For some toxins, the three-dimensional structure has been solved by X-ray diffraction and NMR spectroscopy. A constant structural motif has been found in all of them, consisting of one or two short segments of alpha-helix plus a triple-stranded beta-sheet, connected by variable regions forming loops (turns). Physiological experiments have shown that these toxins are modifiers of the gating mechanism of the Na+-channel function, affecting either the inactivation (alpha-toxins) or the activation (beta-toxins) kinetics of the channels. Many functional variations of these peptides have been demonstrated, which include not only the classical alpha- and beta-types, but also the species specificity of their action. There are peptides that bind or affect the function of Na+-channels from different species (mammals, insects or crustaceans) or are toxic to more than one group of animals. Based on functional and structural features of the known toxins, a classification containing 10 different groups of toxins is proposed in this review. Attempts have been made to correlate the presence of certain amino acid residues or 'active sites' of these peptides with Na+-channel functions. Segments containing positively charged residues in special locations, such as the five-residue turn, the turn between the second and the third beta-strands, the C-terminal residues and a segment of the N-terminal region from residues 2-11, seems to be implicated in the activity of these toxins. However, the uncertainty, and the limited success obtained in the search for the site through which these peptides bind to the channels, are mainly due to the lack of an easy method for expression of cloned genes to produce a well-folded, active peptide. Many scorpion toxin coding genes have been obtained from cDNA libraries and from polymerase chain reactions using fragments of scorpion DNAs, as templates. The presence of an intron at the DNA level, situated in the middle of the signal peptide, has been demonstrated.

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Distribution and function of voltage-gated sodium channels in the nervous system

Jun Jun Wang, Shao-Wu Ou, Yun-Jie Wang (2017)

Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail.

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Characterization of endogenous calcium responses in neuronal cell lines.

Irina Vetter, Richard J. Lewis (2010)

An increasing number of putative therapeutic targets have been identified in recent years for the treatment of neuronal pathophysiologies including pain, epilepsy, stroke and schizophrenia. Many of these targets signal through calcium (Ca(2+)), either by directly facilitating Ca(2+) influx through an ion channel, or through activation of G proteins that couple to intracellular Ca(2+) stores or voltage-gated Ca(2+) channels. Immortalized neuronal cell lines are widely used models to study neuropharmacology. However, systematic pharmacological characterization of the receptors and ion channels expressed in these cell lines is lacking. In this study, we systematically assessed endogenous Ca(2+) signaling in response to addition of agonists at potential therapeutic targets in a range of cell lines of neuronal origin (ND7/23, SH-SY5Y, 50B11, F11 and Neuro2A cells) as well as HEK293 cells, a cell line commonly used for over-expression of receptors and ion channels. This study revealed a remarkable diversity of endogenous Ca(2+) responses in these cell lines, with one or more cell lines responding to addition of trypsin, bradykinin, ATP, nicotine, acetylcholine, histamine and neurotensin. Subtype specificity of these responses was inferred from agonist potency and the effect of receptor subtype specific antagonist. Surprisingly, HEK293 and SH-SY5Y cells responded to the largest number of agonists with potential roles in neuronal signaling. These findings have implications for the heterologous expression of neuronal receptors and ion channels in these cell lines, and highlight the potential of neuron-derived cell lines for the study of a range of endogenously expressed receptors and ion channels that signal through Ca(2+). Crown Copyright 2009. Published by Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Rita de Cássia Collaço:

ORCID: http://orcid.org/0000-0002-2826-1603

rcollaco@unicamp.br , cassia.collaco@gmail.com

Journal

Journal ID (nlm-ta): Arch Toxicol

Journal ID (iso-abbrev): Arch. Toxicol

Title: Archives of Toxicology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0340-5761

ISSN (Electronic): 1432-0738

Publication date (Electronic): 16 June 2020

Publication date PMC-release: 16 June 2020

Publication date (Print): 2020

Volume: 94

Issue: 9

Pages: 3315-3327

Affiliations

[1 ]GRID grid.411087.b, ISNI 0000 0001 0723 2494, Department of Pharmacology, Faculty of Medical Sciences, , State University of Campinas (UNICAMP), ; Campinas, SP Brazil

[2 ]GRID grid.11984.35, ISNI 0000000121138138, Strathclyde Institute of Pharmacy and Biomedical Sciences, , University of Strathclyde, ; Glasgow, UK

[3 ]GRID grid.412409.a, ISNI 0000 0001 2289 0436, São Francisco University (USF), ; Bragança Paulista, SP Brazil

[4 ]GRID grid.418514.d, ISNI 0000 0001 1702 8585, Laboratory of Pharmacology, Division for Scientific Development, , Butantan Institute, ; São Paulo, SP Brazil

Author information

Rita de Cássia Collaço http://orcid.org/0000-0002-2826-1603

Stephen Hyslop http://orcid.org/0000-0002-9293-3638

Thalita Rocha http://orcid.org/0000-0002-2731-9586

Valquiria A. C. Dorce http://orcid.org/0000-0002-0626-0693

Edward G. Rowan http://orcid.org/0000-0002-9960-3308

Edson Antunes http://orcid.org/0000-0003-2201-8247

Article

Publisher ID: 2799

DOI: 10.1007/s00204-020-02799-y

PMC ID: 7415753

PubMed ID: 32548756

SO-VID: bfe307fe-6578-4ada-91d9-10f7a8148be7

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 February 2020

Date accepted : 28 May 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;

Award ID: 2016/11319-6; 2016/23829-9

Award ID: 2017/15175-1

Award Recipient : Rita de Cássia Collaço Edson Antunes

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ScienceOpen disciplines: Toxicology

Keywords: autonomic neurotransmission,voltage-gated sodium channel,tetrodotoxin,nd7-23 cells,electrophysiology

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ScienceOpen disciplines: Toxicology

Keywords: autonomic neurotransmission, voltage-gated sodium channel, tetrodotoxin, nd7-23 cells, electrophysiology

Neurotoxicity of Tityus bahiensis (brown scorpion) venom in sympathetic vas deferens preparations and neuronal cells

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Journal of the Netherlands Society of Toxicology

Most cited references 32

Scorpion toxins specific for Na+-channels

Distribution and function of voltage-gated sodium channels in the nervous system

Characterization of endogenous calcium responses in neuronal cell lines.

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