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

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 Neumaier

doi:10.1016/j.mcn.2019.03.003

Modulation of Ca_v2.3 channels by unconjugated bilirubin (UCB) - Candidate mechanism for UCB-induced neuromodulation and neurotoxicity

Mol Cell Neurosci. 2019 Apr:96:35-46. doi: 10.1016/j.mcn.2019.03.003. Epub 2019 Mar 12.

Affiliations

¹ Institute for Neurophysiology, University of Cologne, Germany; Department of Neurosurgery, RWTH Aachen University, Germany. Electronic address: walbanna@ukaachen.de.
² Institute for Neurophysiology, University of Cologne, Germany.
³ Department of Neurosurgery, RWTH Aachen University, Germany.
⁴ Institute for Neurophysiology, University of Cologne, Germany; Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁵ Department of Medical Engineering and Technomathematics, FH Aachen University of Applied Sciences, Germany.
⁶ Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁷ Institute for Neurophysiology, University of Cologne, Germany. Electronic address: toni.schneider@uni-koeln.de.
⁸ Institute for Neurophysiology, University of Cologne, Germany. Electronic address: felix@neumaier-net.de.

PMID: 30877033
DOI: 10.1016/j.mcn.2019.03.003

Abstract

Elevated 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 Ca_v2.3 + β₃ channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Ca_v2.3-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 administered UCB (U/A = 0.5) has recently been shown to affect transsynaptic signaling in the isolated vertebrate retina. The present report reveals that sustained exposure of the murine retina to UCB significantly suppresses also late responses of the inner retina (b-wave) from wildtype compared to Ca_v2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Ca_v2.3 channels. Together, these findings show that UCB affects cloned and native Ca_v2.3 channels at clinically relevant U/A molar ratios and indicate that supersaturation of albumin is not required for modulation but associated with a loss of channel functional that could contribute to chronic neuronal dysfunction.

Keywords: Hemoglobin metabolism; Jaundice; Membrane lipid perturbation; Murine electroretinogram; Photo-sensitization; UCB:albumin molar ratio.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials
Animals
Bilirubin / pharmacology*
Bilirubin / toxicity
Calcium Channels, R-Type / metabolism*
Cation Transport Proteins / metabolism*
HEK293 Cells
Humans
Male
Mice
Retina / drug effects*
Retina / metabolism
Retina / physiology

Substances

Cacna1e protein, mouse
Calcium Channels, R-Type
Cation Transport Proteins
Bilirubin