Cargando…
Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity
Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca(2...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787254/ https://www.ncbi.nlm.nih.gov/pubmed/31601780 http://dx.doi.org/10.1038/s41419-019-1979-1 |
_version_ | 1783458226736463872 |
---|---|
author | Shi, Hao-Song Lai, Ke Yin, Xin-Lu Liang, Min Ye, Hai-Bo Shi, Hai-Bo Wang, Lu-Yang Yin, Shan-Kai |
author_facet | Shi, Hao-Song Lai, Ke Yin, Xin-Lu Liang, Min Ye, Hai-Bo Shi, Hai-Bo Wang, Lu-Yang Yin, Shan-Kai |
author_sort | Shi, Hao-Song |
collection | PubMed |
description | Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca(2+) overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 μM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca(2+) dependent because preloading MVN neurons with the Ca(2+) buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice. |
format | Online Article Text |
id | pubmed-6787254 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67872542019-10-11 Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity Shi, Hao-Song Lai, Ke Yin, Xin-Lu Liang, Min Ye, Hai-Bo Shi, Hai-Bo Wang, Lu-Yang Yin, Shan-Kai Cell Death Dis Article Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca(2+) overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 μM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca(2+) dependent because preloading MVN neurons with the Ca(2+) buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice. Nature Publishing Group UK 2019-10-10 /pmc/articles/PMC6787254/ /pubmed/31601780 http://dx.doi.org/10.1038/s41419-019-1979-1 Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Shi, Hao-Song Lai, Ke Yin, Xin-Lu Liang, Min Ye, Hai-Bo Shi, Hai-Bo Wang, Lu-Yang Yin, Shan-Kai Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
title | Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
title_full | Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
title_fullStr | Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
title_full_unstemmed | Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
title_short | Ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
title_sort | ca(2+)-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787254/ https://www.ncbi.nlm.nih.gov/pubmed/31601780 http://dx.doi.org/10.1038/s41419-019-1979-1 |
work_keys_str_mv | AT shihaosong ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT laike ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT yinxinlu ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT liangmin ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT yehaibo ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT shihaibo ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT wangluyang ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity AT yinshankai ca2dependentrecruitmentofvoltagegatedsodiumchannelsunderliesbilirubininducedoverexcitationandneurotoxicity |