Universität zu Köln

Albanna, Walid ORCID: 0000-0001-9986-8739, Lueke, Jan Niklas, Schubert, Gerrit Alexander ORCID: 0000-0001-9135-6042, Dibue-Adjei, Maxine, Kotliar, Konstantin, Hescheler, Juergen, Clusmann, Hans, Steiger, Hans-Jakob, Haenggi, Daniel, Kamp, Marcel A., Schneider, Toni and Neumaier, Felix ORCID: 0000-0002-6376-6391 (2019). Modulation of Ca(v)2.3 channels by unconjugated bilirubin (UCB) - Candidate mechanism for UCB-induced neuromodulation and neurotoxicity. Mol. Cell. Neurosci., 96. S. 35 - 47. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1095-9327

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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(v)2.3 + beta(3) channel complexes and ex vivo electroretinograms (ERGs) from wildtype and Ca(v)2.3-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(v)2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Ca(v)2.3 channels. Together, these findings show that UCB affects cloned and native Ca(v)2.3 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Albanna, Walid UNSPECIFIED orcid.org/0000-0001-9986-8739 UNSPECIFIED Lueke, Jan Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schubert, Gerrit Alexander UNSPECIFIED orcid.org/0000-0001-9135-6042 UNSPECIFIED Dibue-Adjei, Maxine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kotliar, Konstantin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Clusmann, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Steiger, Hans-Jakob UNSPECIFIED UNSPECIFIED UNSPECIFIED Haenggi, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamp, Marcel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Toni UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumaier, Felix UNSPECIFIED orcid.org/0000-0002-6376-6391 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-151702
DOI:	10.1016/j.mcn.2019.03.003
Journal or Publication Title:	Mol. Cell. Neurosci.
Volume:	96
Page Range:	S. 35 - 47
Date:	2019
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1095-9327
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Medicine > Physiologie und Pathophysiologie > Institut für Neurophysiologie
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CALCIUM-CHANNELS; PROTEIN-PHOSPHORYLATION; PHOTODYNAMIC-ACTION; ISOLATED MEMBRANE; ALBUMIN BINDING; SERUM-ALBUMIN; TOXICITY; MICE; AGGREGATION; DISRUPTION Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15170