Universität zu Köln

Neumaier, Felix ORCID: 0000-0002-6376-6391, Akhtar-Schaefer, Isha, Lueke, Jan Niklas, Dibue-Adjei, Maxine, Hescheler, Juergen and Schneider, Toni ORCID: 0000-0003-2816-2696 (2018). Reciprocal modulation of Ca(v)2.3 voltage-gated calcium channels by copper(II) ions and kainic acid. J. Neurochem., 147 (3). S. 310 - 323. HOBOKEN: WILEY. ISSN 1471-4159

Full text not available from this repository.

Abstract

Kainic acid (KA) is a potent agonist at non-N-methyl-D-aspartate (non-NMDA) ionotropic glutamate receptors and commonly used to induce seizures and excitotoxicity in animal models of human temporal lobe epilepsy. Among other factors, Ca(v)2.3 voltage-gated calcium channels have been implicated in the pathogenesis of KA-induced seizures. At physiologically relevant concentrations, endogenous trace metal ions (Cu2+, Zn2+) occupy an allosteric binding site on the domain I gating module of these channels and interfere with voltage-dependent gating. Using whole-cell patch-clamp recordings in human embryonic kidney (HEK-293) cells stably transfected with human Ca(v)2.3d and (3)-subunits, we identified a novel, glutamate receptor-independent mechanism by which KA can potently sensitize these channels. Our findings demonstrate that KA releases these channels from the tonic inhibition exerted by low nanomolar concentrations of Cu2+ and produces a hyperpolarizing shift in channel voltage-dependence by about 10 mV, thereby reconciling the effects of Cu2+ chelation with tricine. When tricine was used as a surrogate to study the receptor-independent action of KA in electroretinographic recordings from the isolated bovine retina, it selectively suppressed a late b-wave component, which we have previously shown to be enhanced by genetic or pharmacological ablation of Ca(v)2.3 channels. Although the pathophysiological relevance remains to be firmly established, we speculate that reversal of Cu2+-induced allosteric suppression, presumably via formation of stable kainate-Cu2+ complexes, could contribute to the receptor-mediated excitatory effects of KA. In addition, we discuss experimental implications for the use of KA invitro, with particular emphasis on the seemingly high incidence of trace metal contamination in common physiological solutions.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Neumaier, Felix UNSPECIFIED orcid.org/0000-0002-6376-6391 UNSPECIFIED Akhtar-Schaefer, Isha UNSPECIFIED UNSPECIFIED UNSPECIFIED Lueke, Jan Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Dibue-Adjei, Maxine UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Toni UNSPECIFIED orcid.org/0000-0003-2816-2696 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-167700
DOI:	10.1111/jnc.14546
Journal or Publication Title:	J. Neurochem.
Volume:	147
Number:	3
Page Range:	S. 310 - 323
Date:	2018
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1471-4159
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 AFFINITY ZINC INHIBITION; B-WAVE AMPLITUDE; NEURONAL DEATH; CA2+ CHANNELS; BOVINE RETINA; AMINO-ACIDS; KAINATE; EXCITOTOXICITY; CHELATION; CELLS Multiple languages Biochemistry & Molecular Biology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16770