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 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.

Phycocyanobilin reduces brain injury after endothelin‐1‐ induced focal cerebral ischaemia

“…Furthermore, PCB has demonstrated strong antioxidant, anti‐inflammatory and immunomodulatory attributes, also observed in an ischaemic penumbra model of brain hypoperfusion, and against EAE in mice when it was administered orally . Given the neurotoxicity risks associated with bilirubin overload, and that the Spirulina platensis extract, a natural source of PCB, holds the generally recognized as safe (GRAS) condition granted by the US Food and Drug Administration, this previous paper suggests that PCB may be a plausible anti‐stroke drug candidate to introduce in clinical practice.…”

Unconjugated bilirubin modulates neuronal signaling only in wild‐type mice, but not after ablation of the R‐type/Cav2.3 voltage‐gated calcium channel

“…Based on this recommendation, UCB/albumin ratio in our setup has been chosen as a molar ratio of smaller than one to achieve physiological conditions. Acute administrations of high UCB concentration without albumin cause Ca 2+ overload and subsequent neuronal vulnerability primarily by targeting P/Q‐type Ca 2+ channels on auditory brain regions, via Ca 2+ and calmodulin‐dependent processes . Such high concentration of UCB was prevented in the present study.…”

“…Previous investigations have found bilirubin levels in CSF to be 5‐fold increase in aneurysmal SAH patients with vasospasm compared to healthy controls . BMHDPs can affect various pathological processes, among others, the expression of voltage‐gated calcium channels (VGCCs) such as P‐/Q‐type and R‐type calcium channels (Ca v 2.3 channels), the latter previously assumed to be associated with delayed cerebral vasospasm . Furthermore, mediation of vasoconstriction in smaller arteries (100‐200 μm) by Ca v 2.3 channels is also assumed after SAH .…”

Ca2+-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity

“…Nearly 85% of newborns are affected with neonatal hyperbilirubinemia and clinical jaundice. Acute bilirubin (BIL) encephalopathy, if untreated, may progress to kernicterus, characterized by impairments in auditory perception, body movement, and ocular control 1,2 . Central vestibular neurons are particularly vulnerable to bilirubin-induced neurotoxicity 3–5 .…”