Bilirubin augments Ca(2+) load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels.
Bilirubin augments Ca(2+) load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels.
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DOI：
10.1038/s41598-017-00275-9
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发表时间：
2017-03-27
影响因子：
4.6
通讯作者：
Yin SK
中科院分区：
文献类型：
--
作者：
Liang M;Yin XL;Shi HB;Li CY;Li XY;Song NY;Shi HS;Zhao Y;Wang LY;Yin SK
新生儿大脑特别容易受到病理性胆红素水平的影响，胆红素会升高细胞内钙离子并使其超载，从而导致神经毒性。然而，电压门控钙通道(VGCC)是如何参与过量钙内流的尚不清楚。通过对新生大鼠(P4-17)耳蜗腹核丛状细胞的电压钳记录，发现VGCC的总钙电流密度比P4-17增加了一倍多，但VGCC亚型的相对重量变化很大，在P4-6的T、L、N、P/Q和R型之间相对持平，而在P15-17的Vcn中以L、N、R为主。令人惊讶的是，急性给予胆红素增加了由高电压激活(HVA)P/Q型钙电流特异性介导的VGCC电流。细胞内钙缓冲液EGTA或钙调素抑制肽可减弱这种增加。我们的发现表明，急性胆红素暴露增加了VGCC电流，主要是通过钙离子和钙调素依赖机制靶向P/Q型钙通道，使过量的钙离子淹没神经元。由于P/Q亚型钙通道在新生神经元(如P4-6)中比晚期更为显著，我们认为这种P/Q型钙电流的亚型特异性增强可能是听觉和其他脑区神经元对高胆红素血症早期易感性的原因之一。
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.