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

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

Research output: Contribution to journalArticle

99 Scopus citations

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.

Original languageEnglish (US)
Article number304
Number of pages1
JournalBasic research in cardiology
Volume107
Issue number6
DOIs
StatePublished - Nov 1 2012

Keywords

  • Cardiomyocytes
  • Connexin 43
  • Connexin hemichannel
  • Mimetic peptides
  • Single channel

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Wang, N., De Bock, M., Antoons, G., Gadicherla, A. K., Bol, M., Decrock, E., Evans, W. H., Sipido, K. R., Bukauskas, F. F., & Leybaert, L. (2012). Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation. Basic research in cardiology, 107(6), [304]. https://doi.org/10.1007/s00395-012-0304-2