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

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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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Acknowledgments

This work was supported by the Interuniversity Attraction Poles Program (Belgian Science Policy Project P6/31 and P7/10 to K.R. Sipido and L. Leybaert), the Fund for Scientific Research Flanders (FWO Grant Numbers G.0140.08, 3G.0134.09 and G.0298.11 to L. Leybaert) and supported by NIH Grants (R01NS072238 and RO1HL084464 to F.F. Bukauskas).

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  1. Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185 (Block B-Rm 031), 9000, Ghent, Belgium

    Nan Wang, Marijke De Bock, Ashish K. Gadicherla, Mélissa Bol, Elke Decrock & Luc Leybaert

  2. Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Gudrun Antoons

  3. Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, Wales, UK

    William Howard Evans

  4. Department for Experimental Cardiology, K.U.Leuven, Herestraat 49, 3000, Leuven, Belgium

    Karin R. Sipido

  5. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA

    Feliksas F. Bukauskas

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Wang, N., De Bock, M., Antoons, G. et al. Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation. Basic Res Cardiol 107, 304 (2012). https://doi.org/10.1007/s00395-012-0304-2

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