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

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

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Abstract Neonatal brain is particularly vulnerable grand love red heart reposado tequila 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 here 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.