Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages

Pucca, Manuela Berto; Peigneur, Steve; Cologna, Camila Takeno; Cerni, Felipe Augusto; Zoccal, Karina Furlani; Bordon, Karla de Castro Figueiredo; Faccioli, Lúcia Helena; Tytgat, Jan; Arantes, Eliane Candiani

doi:10.1016/j.biochi.2015.04.010

Cited by 30 publications

(28 citation statements)

References 66 publications

(62 reference statements)

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“…Tityus serrulatus venom is considered a rich source of neurotoxins specific for sodium and potassium channels . Among them, Ts6 and Ts15 are capable of blocking Kv1.3 channels .…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

et al. 2016

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SummaryThe voltage-gated potassium channel Kv1.3 is a novel target for immunomodulation of autoreactive effector memory T cells, which play a major role in the pathogenesis of autoimmune diseases. In this study, the Ts6 and Ts15 toxins isolated from Tityus serrulatus (Ts) were investigated for their immunosuppressant roles on CD4 + cell subsets: naive, effector (T EF ), central memory (T CM ) and effector memory (T EM ). The electrophysiological assays confirmed that both toxins were able to block Kv1.3 channels. Interestingly, an extended Kv channel screening shows that Ts15 blocks Kv2.1 channels. Ts6 and Ts15 significantly inhibit the proliferation of T EM cells and interferon-c production; however, Ts15 also inhibits other CD4 + cell subsets (naive, T EF and T CM ). Based on the Ts15 inhibitory effect of proliferation of all CD4 + cell subsets, and based on its blocking effect on Kv2.1, we investigated the Kv2.1 expression in T cells. The assays showed that CD4 + and CD8 + cells express the Kv2.1 channels mainly extracellularly with T CM cells expressing the highest number of Kv2.1 channels. We also provide in vivo experimental evidence to the protective effect of Ts6 and Ts15 on delayed-type hypersensitivity reaction. Altogether, this study presents the immunosuppressive behaviour of Ts6 and Ts15 toxins, indicating that these toxins could be promising candidates for autoimmune disease therapy. Moreover, this is the first report illustrating the involvement of a novel K + channel subtype, Kv2.1, and its distribution in T-cell subsets.

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“…Tityus serrulatus venom is considered a rich source of neurotoxins specific for sodium and potassium channels . Among them, Ts6 and Ts15 are capable of blocking Kv1.3 channels .…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

et al. 2016

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“…Diversos estudos envolvendo neurotoxinas de Ts e canais iônicos já foram relatados na literatura, as quais já demonstraram interagir com canais para sódio e para potássio dependentes de voltagem (Cerni et al, 2015;Cerni et al, 2014;Cologna et al, 2011;Peigneur et al, 2015;Pucca et al, 2016a;Pucca et al, 2016b;Pucca et al, 2015b;Pucca et al, 2015d) 1.7.1. Neurotoxinas de T. serrulatus com ação em canais para sódio dependentes de voltagem (Navs)…”

Section: Canais Iônicos Sensíveis a Voltagem E Toxinas Escorpiônicasunclassified

“…No entanto, é capaz de induzir a liberação de catecolaminas, acetilcolina (ACh), óxido nítrico (NO), ácido gamaaminobutírico (GABA), aspartato (Asp) e glutamato (Glu), por agirem em canais para sódio (Bordon et al, 2015). Ts4 demonstrou alterar especificamente canais Nav1.6, enquanto a toxina Ts5 é capaz de inibir a inativação dos canais Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6 e Nav1.7 (Pucca et al, 2015b;Pucca et al, 2015d).…”

Section: Canais Iônicos Sensíveis a Voltagem E Toxinas Escorpiônicasunclassified

“…Estudos de eletrofisiologia utilizando a técnica de voltagem clamp com dois microelétrodos, demonstraram que a peçonha de Ts apresenta quatro neurotoxinas (Ts1, Ts2, Ts4 e Ts5) com ação em Navs relacionados com a dor (Cologna et al, 2012;Peigneur et al, 2015;Pucca et al, 2015b;Pucca et al, 2015d). Além disso, a toxina Ts8 demonstrou interagir com canais Kv4.2, o único canal para potássio diretamente relacionado com a algesia (Pucca et al, 2016b).…”

Section: A Hiperalgesia Induzida Pela Peçonha De T Serrulatusunclassified

“…A toxina Ts6 diminuiu a produção de TNF-α e induziu o aumento de IL-6 e NO. A Ts5 mostrou possuir efeito pró-inflamatório, uma vez que induziu o aumento da produção de TNF-α e IL-6 em macrófagos através de diferentes vias de sinalização: direta e indireta (Pucca et al, 2015d;Zoccal et al, 2011a;Zoccal et al, 2013a). Ainda, foi demonstrado que a peçonha de Ts é capaz de ativar PPAR-γ e induzir a produção de prostaglandina (PGE2) e leucotrieno (LTB4) .…”

Section: A Modulação Da Resposta Imune Pela Peçonha E Toxinas De T Sunclassified

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Isolamento, caracterização molecular e funcional de uma nova toxina presente na peçonha do escorpião Tityus serrulatus

Cerni¹

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À minha orientadora Eliane Candiani Arantes, pela oportunidade, confiança, amizade, e por todo conhecimento compartilhado. À FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) pela bolsa de doutorado no Brasil (Processo Nᵒ 2012/13590-8) e no exterior (BEPE Nᵒ 2013/21342-7). Sem seu auxílio financeiro esse projeto não teria se concretizado. Ao Departamento de Toxicologia da Faculdade de Ciências Farmacêuticas de Ribeirão Preto e, em especial à Rose. Às funcionárias do Laboratório de Toxina Animais, Karla e Iara, por toda a ajuda técnica no laboratório. Aos meus amigos do laboratório de Toxina Animais pela amizade ao longo desse período. Aos integrantes do laboratório de toxicologia da Universidade Católica de Leuven (KULeuven, Bélgica), em especial ao professor Jan Tytgat pela oportunidade de trabalhar em seu laboratório e ao técnico Steve pelo apoio durante o período de doutorado sanduiche. Aos colaboradores da Faculdade de Medicina de Ribeirão Preto, professores Thiago M. Cunha e José Carlos Filho (Zeca), técnica Ieda e ao aluno Douglas. Aos colaboradores da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, em especial a doutora Karina F. Zoccal e à professora Fabiane. À minha família pelo incentivo, compreensão e carinho. Em especial a minha esposa Manuela B. Pucca, pelo apoio cientifico e emocional que foram a base do sucesso desse trabalho.

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Differential effect of Androctonus australis hector venom components on macrophage KV channels: electrophysiological characterization

et al. 2018

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Neurotoxins of scorpion venoms modulate ion channels. Voltage-gated potassium (K) channels regulate the membrane potential and are involved in the activation and proliferation of immune cells. Macrophages are key components of the inflammatory response induced by scorpion venom. The present study was undertaken to investigate the effect of Androctonus australis hector (Aah) venom on K channels in murine resident peritoneal macrophages. The cytotoxicity of the venom was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) -based assay and electrophysiological recordings were performed using the whole-cell patch clamp technique. High doses of Aah venom (50, 125, 250 and 500 µg/ml) significantly decreased cell viability, while concentrations of 0.1-25 µg/ml were not cytotoxic towards peritoneal macrophages. Electrophysiological data revealed a differential block of K current between resting and LPS-activated macrophages. Aah venom significantly reduced K current amplitude by 62.5 ± 4.78% (n = 8, p < 0.05), reduced the use-dependent decay of the current, decreased the degree of inactivation and decelerated the inactivation process of K current in LPS-activated macrophages. Unlike cloned K1.5 channels, Aah venom exerted a similar blocking effect on K1.3 compared to K current in LPS-activated macrophages, along with a hyperpolarizing shift in the voltage dependence of K1.3 inactivation, indicating a direct mechanism of current inhibition by targeting K1.3 subunits. The obtained results, demonstrating that Aah venom differentially targets K channels in macrophages, suggest differential outcomes for their inhibitions, and that further investigations of scorpion venom immunomodulatory potential are required.

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Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages

Cited by 30 publications

References 66 publications

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

Isolamento, caracterização molecular e funcional de uma nova toxina presente na peçonha do escorpião Tityus serrulatus

Differential effect of Androctonus australis hector venom components on macrophage KV channels: electrophysiological characterization

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Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages

Cited by 30 publications

References 66 publications

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells

Isolamento, caracterização molecular e funcional de uma nova toxina presente na peçonha do escorpião Tityus serrulatus

Differential effect of Androctonus australis hector venom components on macrophage KV channels: electrophysiological characterization

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Resources

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Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells