Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) – Candidate mechanism for UCB-induced neuromodulation and neurotoxicity

Publication date: Available online 12 March 2019Source: Molecular and Cellular NeuroscienceAuthor(s): Walid Albanna, Jan Niklas Lüke, Gerrit Alexander Schubert, Maxine Dibué-Adjei, Konstantin Kotliar, Jürgen Hescheler, Hans Clusmann, Hans-Jakob Steiger, Daniel Hänggi, Marcel A. Kamp, Toni Schneider, Felix NeumaierAbstractElevated levels of unbound unconjugated bilirubin (UCB) can lead to bilirubin encephalopathy and kernicterus. In spite of a large number of studies demonstrating UCB-induced changes in central neurotransmission, it is still unclear whether these effects involve alterations in the function of specific ion channels. To assess how different UCB concentrations and UCB:albumin (U/A) molar ratios affect neuronal R-type voltage-gated Ca2+ channels, we evaluated their effects on whole-cell currents through recombinant Cav2.3 + β3 channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Cav2.3-deficient mice. Our findings show that modestly elevated levels of unbound UCB (U/A = 0.5) produce subtle but significant changes in the voltage-dependence of activation and prepulse inactivation, resulting in a stimulation of currents activated by weak depolarization and inhibition at potentials on the plateau of the activation curve. Saturation of the albumin binding capacity (U/A = 1) produced additional suppression that became significant when albumin was omitted completely and might involve a complete loss of channel function.Acutely admini...
Source: Molecular and Cellular Neuroscience - Category: Neuroscience Source Type: research