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01-11-2012 | Original Contribution

Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca²⁺ elevation

Authors: Nan Wang, Marijke De Bock, Gudrun Antoons, Ashish K. Gadicherla, Mélissa Bol, Elke Decrock, William Howard Evans, Karin R. Sipido, Feliksas F. Bukauskas, Luc Leybaert

Published in: Basic Research in Cardiology | Issue 6/2012

Abstract

Connexin mimetic peptides (CxMPs), such as Gap26 and Gap27, are known as inhibitors of gap junction channels but evidence is accruing that these peptides also inhibit unapposed/non-junctional hemichannels (HCs) residing in the plasma membrane. We used voltage clamp studies to investigate the effect of Gap26/27 at the single channel level. Such an approach allows unequivocal identification of HC currents by their single channel conductance that is typically ~220 pS for Cx43. In HeLa cells stably transfected with Cx43 (HeLa-Cx43), Gap26/27 peptides inhibited Cx43 HC unitary currents over minutes and increased the voltage threshold for HC opening. By contrast, an elevation of intracellular calcium ([Ca²⁺]_i) to 200–500 nM potentiated the unitary HC current activity and lowered the voltage threshold for HC opening. Interestingly, Gap26/27 inhibited the Ca²⁺-potentiated HC currents and prevented lowering of the voltage threshold for HC opening. Experiments on isolated pig ventricular cardiomyocytes, which display strong endogenous Cx43 expression, demonstrated voltage-activated unitary currents with biophysical properties of Cx43 HCs that were inhibited by small interfering RNA targeting Cx43. As observed in HeLa-Cx43 cells, HC current activity in ventricular cardiomyocytes was potentiated by [Ca²⁺]_i elevation to 500 nM and was inhibited by Gap26/27. Our results indicate that under pathological conditions, when [Ca²⁺]_i is elevated, Cx43 HC opening is promoted in cardiomyocytes and CxMPs counteract this effect.

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Title: Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation
Authors: Nan Wang
Marijke De Bock
Gudrun Antoons
Ashish K. Gadicherla
Mélissa Bol
Elke Decrock
William Howard Evans
Karin R. Sipido
Feliksas F. Bukauskas
Luc Leybaert
Publication date: 01-11-2012
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 6/2012
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0304-2

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Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca²⁺ elevation

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