Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels

Cann, Marianne van; Kuzmenkov, Alexey I.; Isensee, Jörg; Andreev-Andrievskiy, Alexander; Peigneur, Steve; Khusainov, Georgii; Berkut, Antonina A.; Tytgat, Jan; Vassilevski, Alexander A.; Hucho, Tim

doi:10.1111/febs.15593

Cited by 6 publications

(9 citation statements)

References 67 publications

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“…Many of those factors, including depolarization 7,27,29 as recently shown by us, sensitize through intracellular cascades such as the PKA pathway. 3,7,20,22,23,27,29,36,59,65,77,82 Accordingly, detecting PKA-II activity with conformation-specific antibodies in rodent or iPSCderived nociceptors allows to monitor PKA-mediated sensitization stimuli as well as desensitizing opioid activity. 6,7,[29][30][31][32][33][34][35]78 Protocols to generate human nociceptors from human pluripotent stem cells (PSCs) have been developed based on small-molecule treatment, transcription factor overexpression, or combinations of both.…”

Section: Introductionmentioning

confidence: 82%

“…33,44,58,70 Nociceptive neuron activity can be increased by a plethora of factors such as inflammatory interleukins, prostaglandins, and growth factors. Many of those factors, including depolarization 7,27,29 as recently shown by us, sensitize through intracellular cascades such as the PKA pathway. 3,7,20,22,23,27,29,36,59,65,77,82 Accordingly, detecting PKA-II activity with conformation-specific antibodies in rodent or iPSC-derived nociceptors allows to monitor PKA-mediated sensitization stimuli as well as desensitizing opioid activity.…”

Section: Introductionmentioning

confidence: 90%

“…When PKA-II signaling emerges in hiPSCdNs is not known. We adapted an HCS microscopy-based method for monitoring the activation process of endogenous PKA-II signaling activity 6,7,[29][30][31][32][33][34][35]78 in hiPSCdN cultures after 16 days, 35 days, 49 days, and 70 days of differentiation. Software-based identification of objects in neuronal cultures with dense neurite networks was achieved by establishing fluorescence detection of Nissl staining of neuronal cell bodies for automated image analysis (Fig.…”

Section: Receptor-independent Intracellular Protein Kinase a Type II ...mentioning

confidence: 99%

“…3,7,20,22,23,27,29,36,59,65,77,82 Accordingly, detecting PKA-II activity with conformation-specific antibodies in rodent or iPSC-derived nociceptors allows to monitor PKA-mediated sensitization stimuli as well as desensitizing opioid activity. 6,7,29–35,78…”

Section: Introductionmentioning

confidence: 99%

“…3,7,20,22,23,27,29,36,59,65,77,82 Accordingly, detecting PKA-II activity with conformation-specific antibodies in rodent or iPSCderived nociceptors allows to monitor PKA-mediated sensitization stimuli as well as desensitizing opioid activity. 6,7,[29][30][31][32][33][34][35]78 Protocols to generate human nociceptors from human pluripotent stem cells (PSCs) have been developed based on small-molecule treatment, transcription factor overexpression, or combinations of both. 4,12,28,41,42,51,55,63,66,75 Such iPSC-derived nociceptors reflect a large range of nociceptive properties and have been used successfully to model neuropathic pain phenotypes in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell–derived sensory neurons

Röderer

Belu

Heidrich

et al. 2023

Pain

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Induced pluripotent stem cells (iPSCs) have enabled the generation of various difficult-to-access cell types such as human nociceptors. A key challenge associated with human iPSC-derived nociceptors (hiPSCdNs) is their prolonged functional maturation. While numerous studies have addressed the expression of classic neuronal markers and ion channels in hiPSCdNs, the temporal development of key signaling cascades regulating nociceptor activity has remained largely unexplored. In this study, we used an immunocytochemical high-content imaging approach alongside electrophysiological staging to assess metabotropic and ionotropic signaling of large scale–generated hiPSCdNs across 70 days of in vitro differentiation. During this period, the resting membrane potential became more hyperpolarized, while rheobase, action potential peak amplitude, and membrane capacitance increased. After 70 days, hiPSCdNs exhibited robust physiological responses induced by GABA, pH shift, ATP, and capsaicin. Direct activation of protein kinase A type II (PKA-II) through adenylyl cyclase stimulation with forskolin resulted in PKA-II activation at all time points. Depolarization-induced activation of PKA-II emerged after 35 days of differentiation. However, effective inhibition of forskolin-induced PKA-II activation by opioid receptor agonists required 70 days of in vitro differentiation. Our results identify a pronounced time difference between early expression of functionally important ion channels and emergence of regulatory metabotropic sensitizing and desensitizing signaling only at advanced stages of in vitro cultivation, suggesting an independent regulation of ionotropic and metabotropic signaling. These data are relevant for devising future studies into the development and regulation of human nociceptor function and for defining time windows suitable for hiPSCdN-based drug discovery.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 90%

Section: Receptor-independent Intracellular Protein Kinase a Type II ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell–derived sensory neurons

Röderer

Belu

Heidrich

et al. 2023

Pain

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A scorpion toxin affecting sodium channels shows double cis–trans isomerism

Mineev,

Chernykh,

Motov

et al. 2023

FEBS Letters

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Scorpion α‐toxins (α‐NaTx) inhibiting the inactivation of voltage‐gated sodium channels (Nav) are a well‐studied family of small proteins. We previously showed that the structure of α‐NaTx specificity module responsible for selective Nav binding is governed by an interplay between the nest and niche protein motifs. Here, we report the solution structure of the toxin Lqq4 from the venom of the scorpion Leiurus quinquestriatus. Unexpectedly, we find that this toxin presents an ensemble of long‐lived structurally distinct states. We unequivocally assign these states to the alternative configurations (cis–trans isomers) of two peptide bonds: V56–P57 and C17–G18; neither of the cis isomers has been described in α‐NaTx so far. We argue that the native conformational space of α‐NaTx is wider than assumed previously.

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Structure of MeuNaTxα‐1 toxin from scorpion venom highlights the importance of the nest motif

et al. 2021

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Old world scorpions produce an abundance of toxins called α‐NaTx, which interfere with the fast inactivation of voltage‐gated sodium channels. Their selectivity to channels of mammals or insects depends on a part of toxin named the specificity module. We report here the spatial structure of a major and broadly active toxin MeuNaTxα‐1 from the venom of Mesobuthus eupeus. Notably, its specificity module is markedly different from other α‐NaTx with known 3D structure. Close inspection shows that its conformation is a result of an interplay between protein motifs such as the nest and niche, which eventually shape α‐NaTx structural diversity.

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Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels

Cited by 6 publications

References 67 publications

Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell–derived sensory neurons

Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell–derived sensory neurons

A scorpion toxin affecting sodium channels shows double cis–trans isomerism

Structure of MeuNaTxα‐1 toxin from scorpion venom highlights the importance of the nest motif

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