Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels

Abstract Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca2+, leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing volt...

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Autores principales:	Min Liang, Xin-Lu Yin, Hai-Bo Shi, Chun-Yan Li, Xin-Yi Li, Ning-Ying Song, Hao-Song Shi, Yi Zhao, Lu-Yang Wang, Shan-Kai Yin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/15d6104fa7dd465c8f49696ea67b78c5
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spelling	oai:doaj.org-article:15d6104fa7dd465c8f49696ea67b78c52021-12-02T11:40:31ZBilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels10.1038/s41598-017-00275-92045-2322https://doaj.org/article/15d6104fa7dd465c8f49696ea67b78c52017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00275-9https://doaj.org/toc/2045-2322Abstract Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca2+, leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing voltage-clamp recordings from bushy cells in the ventral cochlear nucleus (VCN) in postnatal rat pups (P4-17), we found the total calcium current density was more than doubled over P4-17, but the relative weight of VGCC subtypes changed dramatically, being relatively equal among T, L, N, P/Q and R-type at P4-6 to predominantly L, N, R over T and P/Q at P15-17. Surprisingly, acute administration of bilirubin augmented the VGCC currents specifically mediated by high voltage-activated (HVA) P/Q-type calcium currents. This augment was attenuated by intracellular loading of Ca2+ buffer EGTA or calmodulin inhibitory peptide. Our findings indicate that acute exposure to bilirubin increases VGCC currents, primarily by targeting P/Q-type calcium channels via Ca2+ and calmodulin dependent mechanisms to overwhelm neurons with excessive Ca2+. Since P/Q-subtype calcium channels are more prominent in neonatal neurons (e.g. P4-6) than later stages, we suggest this subtype-specific enhancement of P/Q-type Ca2+ currents likely contributes to the early neuronal vulnerability to hyperbilirubinemia in auditory and other brain regions.Min LiangXin-Lu YinHai-Bo ShiChun-Yan LiXin-Yi LiNing-Ying SongHao-Song ShiYi ZhaoLu-Yang WangShan-Kai YinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Min Liang Xin-Lu Yin Hai-Bo Shi Chun-Yan Li Xin-Yi Li Ning-Ying Song Hao-Song Shi Yi Zhao Lu-Yang Wang Shan-Kai Yin Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
description	Abstract Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca2+, leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing voltage-clamp recordings from bushy cells in the ventral cochlear nucleus (VCN) in postnatal rat pups (P4-17), we found the total calcium current density was more than doubled over P4-17, but the relative weight of VGCC subtypes changed dramatically, being relatively equal among T, L, N, P/Q and R-type at P4-6 to predominantly L, N, R over T and P/Q at P15-17. Surprisingly, acute administration of bilirubin augmented the VGCC currents specifically mediated by high voltage-activated (HVA) P/Q-type calcium currents. This augment was attenuated by intracellular loading of Ca2+ buffer EGTA or calmodulin inhibitory peptide. Our findings indicate that acute exposure to bilirubin increases VGCC currents, primarily by targeting P/Q-type calcium channels via Ca2+ and calmodulin dependent mechanisms to overwhelm neurons with excessive Ca2+. Since P/Q-subtype calcium channels are more prominent in neonatal neurons (e.g. P4-6) than later stages, we suggest this subtype-specific enhancement of P/Q-type Ca2+ currents likely contributes to the early neuronal vulnerability to hyperbilirubinemia in auditory and other brain regions.
format	article
author	Min Liang Xin-Lu Yin Hai-Bo Shi Chun-Yan Li Xin-Yi Li Ning-Ying Song Hao-Song Shi Yi Zhao Lu-Yang Wang Shan-Kai Yin
author_facet	Min Liang Xin-Lu Yin Hai-Bo Shi Chun-Yan Li Xin-Yi Li Ning-Ying Song Hao-Song Shi Yi Zhao Lu-Yang Wang Shan-Kai Yin
author_sort	Min Liang
title	Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
title_short	Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
title_full	Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
title_fullStr	Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
title_full_unstemmed	Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
title_sort	bilirubin augments ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/15d6104fa7dd465c8f49696ea67b78c5
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Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels

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