Universität zu Köln

Neumaier, Felix ORCID: 0000-0002-6376-6391, Alpdogan, Serdar ORCID: 0000-0002-5188-9925, Hescheler, Juergen and Schneider, Toni ORCID: 0000-0003-2816-2696 (2020). Zn2+-induced changes in Ca(v)2.3 channel function: An electrophysiological and modeling study. J. Gen. Physiol., 152 (9). NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-7748

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Abstract

Loosely bound Zn2+ ions are increasingly recognized as potential modulators of synaptic plasticity and neuronal excitability under normal and pathophysiological conditions. Ca(v)2.3 voltage-gated Ca2+ channels are among the most sensitive targets of Zn2+ and are therefore likely to be involved in the neuromodulatory actions of endogenous Zn2+. Although histidine residues on the external side of domain I have been implicated in the effects on Ca(v)2.3 channel gating, the exact mechanisms involved in channel modulation remain incompletely understood. Here, we use a combination of electrophysiological recordings, modification of histidine residues, and computational modeling to analyze Zn2+-induced changes in Ca(v)2.3 channel function. Our most important findings are that multiple high- and low-affinity mechanisms contribute to the net Zn2+ action, that Zn2+ can either inhibit or stimulate Ca2+ influx through Ca(v)2.3 channels depending on resting membrane potential, and that Zn2+ effects may persist for some time even after cessation of the Zn2+ signal. Computer simulations show that (1) most salient features of Ca(v)2.3 channel gating in the absence of trace metals can be reproduced by an obligatory model in which activation of two voltage sensors is necessary to open the pore; and (2) most, but not all, of the effects of Zn2+ can be accounted for by assuming that Zn2+ binding to a first site is associated with an electrostatic modification and mechanical slowing of one of the voltage sensors, whereas Zn2+ binding to a second, lower-affinity site blocks the channel and modifies the opening and closing transitions. While still far from complete, our model provides a first quantitative framework for understanding Zn2+ effects on Ca(v)2.3 channel function and a step toward the application of computational approaches for predicting the complex actions of Zn2+ on neuronal excitability.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Neumaier, Felix UNSPECIFIED orcid.org/0000-0002-6376-6391 UNSPECIFIED Alpdogan, Serdar UNSPECIFIED orcid.org/0000-0002-5188-9925 UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Toni UNSPECIFIED orcid.org/0000-0003-2816-2696 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-320905
DOI:	10.1085/jgp.202012585
Journal or Publication Title:	J. Gen. Physiol.
Volume:	152
Number:	9
Date:	2020
Publisher:	ROCKEFELLER UNIV PRESS
Place of Publication:	NEW YORK
ISSN:	1540-7748
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SYNAPTICALLY RELEASED ZINC; LONG-TERM POTENTIATION; MULTIPLE OPEN STATES; CALCIUM-CHANNELS; CA2+ CHANNELS; ACTIVATION KINETICS; HISTIDINE-RESIDUES; MICE LACKING; HIGH-VOLTAGE; GUINEA-PIG Multiple languages Physiology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32090