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Direct evidence for high affinity blockade of NaV1.6 channel subtype by huwentoxin-IV spider peptide, using multiscale functional approaches.
Neuropharmacology. 2018 05 01; 133:404-414.N

Abstract

The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV1.7 subtype of voltage-gated sodium (NaV) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly-elicited muscle contractile force of isolated mouse hemidiaphragms. These results strongly suggest that the inhibition of nerve-evoked skeletal muscle functioning, produced by HwTx-IV, resulted from a toxin-induced preferential blockade of NaV1.6, compared to NaV1.4, channel subtype. This was confirmed by whole-cell automated patch-clamp experiments performed on human embryonic kidney (HEK)-293 cells overexpressing hNaV1.1-1.8 channel subtypes. HwTx-IV was also approximatively 850 times more efficient to inhibit TTX-sensitive than TTX-resistant sodium currents recorded from mouse dorsal root ganglia neurons. Finally, based on our data, we predict that blockade of the NaV1.6 channel subtype was involved in the in vivo toxicity of HwTx-IV, although this toxicity was more than 2 times lower than that of TTX. In conclusion, our results provide detailed information regarding the effects of HwTx-IV and allow a better understanding of the side-effect mechanisms involved in vivo and of channel subtype interactions resulting from the toxin activity.

Authors+Show Affiliations

Sanofi R & D, Integrated Drug Discovery, In Vitro Biology & Pharmacology, F-94440, Vitry-sur-Seine, France; Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191, Gif sur Yvette, France.Sanofi R & D, Integrated Drug Discovery, In Vitro Biology & Pharmacology, F-94440, Vitry-sur-Seine, France.Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191, Gif sur Yvette, France; Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR CNRS/Université Paris-Sud 9197, Université Paris-Saclay, F-91198, Gif sur Yvette, France.Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191, Gif sur Yvette, France.Sanofi R & D, Integrated Drug Discovery, In Vitro Biology & Pharmacology, F-94440, Vitry-sur-Seine, France.Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191, Gif sur Yvette, France.Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191, Gif sur Yvette, France; Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR CNRS/Université Paris-Sud 9197, Université Paris-Saclay, F-91198, Gif sur Yvette, France. Electronic address: evelyne.benoit@cea.fr.

Pub Type(s)

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

Language

eng

PubMed ID

29474819

Citation

Gonçalves, Tânia C., et al. "Direct Evidence for High Affinity Blockade of NaV1.6 Channel Subtype By huwentoxin-IV Spider Peptide, Using Multiscale Functional Approaches." Neuropharmacology, vol. 133, 2018, pp. 404-414.
Gonçalves TC, Boukaiba R, Molgó J, et al. Direct evidence for high affinity blockade of NaV1.6 channel subtype by huwentoxin-IV spider peptide, using multiscale functional approaches. Neuropharmacology. 2018;133:404-414.
Gonçalves, T. C., Boukaiba, R., Molgó, J., Amar, M., Partiseti, M., Servent, D., & Benoit, E. (2018). Direct evidence for high affinity blockade of NaV1.6 channel subtype by huwentoxin-IV spider peptide, using multiscale functional approaches. Neuropharmacology, 133, 404-414. https://doi.org/10.1016/j.neuropharm.2018.02.016
Gonçalves TC, et al. Direct Evidence for High Affinity Blockade of NaV1.6 Channel Subtype By huwentoxin-IV Spider Peptide, Using Multiscale Functional Approaches. Neuropharmacology. 2018 05 1;133:404-414. PubMed PMID: 29474819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct evidence for high affinity blockade of NaV1.6 channel subtype by huwentoxin-IV spider peptide, using multiscale functional approaches. AU - Gonçalves,Tânia C, AU - Boukaiba,Rachid, AU - Molgó,Jordi, AU - Amar,Muriel, AU - Partiseti,Michel, AU - Servent,Denis, AU - Benoit,Evelyne, Y1 - 2018/02/21/ PY - 2017/10/27/received PY - 2018/01/16/revised PY - 2018/02/19/accepted PY - 2018/2/24/pubmed PY - 2018/11/6/medline PY - 2018/2/24/entrez KW - Cell lines overexpressing Na(V) channel subtypes KW - Electrophysiology KW - Huwentoxin-IV KW - Mouse dorsal root ganglia neurons KW - Mouse neuromuscular excitability KW - Na(V) channel subtypes KW - Voltage-gated sodium channels SP - 404 EP - 414 JF - Neuropharmacology JO - Neuropharmacology VL - 133 N2 - The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV1.7 subtype of voltage-gated sodium (NaV) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly-elicited muscle contractile force of isolated mouse hemidiaphragms. These results strongly suggest that the inhibition of nerve-evoked skeletal muscle functioning, produced by HwTx-IV, resulted from a toxin-induced preferential blockade of NaV1.6, compared to NaV1.4, channel subtype. This was confirmed by whole-cell automated patch-clamp experiments performed on human embryonic kidney (HEK)-293 cells overexpressing hNaV1.1-1.8 channel subtypes. HwTx-IV was also approximatively 850 times more efficient to inhibit TTX-sensitive than TTX-resistant sodium currents recorded from mouse dorsal root ganglia neurons. Finally, based on our data, we predict that blockade of the NaV1.6 channel subtype was involved in the in vivo toxicity of HwTx-IV, although this toxicity was more than 2 times lower than that of TTX. In conclusion, our results provide detailed information regarding the effects of HwTx-IV and allow a better understanding of the side-effect mechanisms involved in vivo and of channel subtype interactions resulting from the toxin activity. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/29474819/Direct_evidence_for_high_affinity_blockade_of_NaV1_6_channel_subtype_by_huwentoxin_IV_spider_peptide_using_multiscale_functional_approaches_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(18)30073-X DB - PRIME DP - Unbound Medicine ER -