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Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides

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Abstract

Co-ordinated electrical activation of the heart is maintained by intercellular coupling of cardiomyocytes via gap junctional channels located in the intercalated disks. These channels consist of two hexameric hemichannels, docked to each other, provided by either of the adjacent cells. Thus, a complete gap junction channel is made from 12 protein subunits, the connexins. While 21 isoforms of connexins are presently known, cardiomyocytes typically are coupled by Cx43 (most abundant), Cx40 or Cx45. Some years ago, antiarrhythmic peptides were discovered and synthesised, which were shown to increase macroscopic gap junction conductance (electrical coupling) and enhance dye transfer (metabolic coupling). The lead substance of these peptides is AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-CONH2), a peptide with a horseshoe-like spatial structure as became evident from two-dimensional nuclear magnetic resonance studies. A stable d-amino-acid derivative of AAP10, rotigaptide, as well as a non-peptide analogue, gap-134, has been developed in recent years. Antiarrhythmic peptides act on Cx43 and Cx45 gap junctions but not on Cx40 channels. AAP10 has been shown to enhance intercellular communication in rat, rabbit and human cardiomyocytes. Antiarrhythmic peptides are effective against ventricular tachyarrhythmias, such as late ischaemic (type IB) ventricular fibrillation, CaCl2 or aconitine-induced arrhythmia. Interestingly, the effect of antiarrhythmic peptides is higher in partially uncoupled cells and was shown to be related to maintained Cx43 phosphorylation, while arrhythmogenic conditions like ischaemia result in Cx43 dephosphorylation and intercellular decoupling. It is still a matter of debate whether these drugs also act against atrial fibrillation. The present review outlines the development of this group of peptides and derivatives, their mode of action and molecular mechanisms, and discusses their possible therapeutic potential.

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Acknowledgements

This study has been supported by the Deutsche Forschungsgemeinschaft (grant to S.D.) and by the Studienstiftung des Deutschen Volkes (grant to A.H.).

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Authors and Affiliations

  1. Clinic for Cardiac Surgery, University of Leipzig, Struempellstr. 39, 04289, Leipzig, Germany

    Stefan Dhein

  2. Heart Centre Leipzig, University of Leipzig, Struempellstr. 39, 04289, Leipzig, Germany

    Stefan Dhein, Joanna Jozwiak, Anna Dietze, Jens Garbade, Markus Barten, Martin Kostelka & Friedrich-Wilhelm Mohr

  3. University Hospital for Children and Adolescents, University of Leipzig, Liebigstr. 20°, 04103, Leipzig, Germany

    Anja Hagen

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Correspondence to Stefan Dhein.

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Dhein, S., Hagen, A., Jozwiak, J. et al. Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn-Schmied Arch Pharmacol 381, 221–234 (2010). https://doi.org/10.1007/s00210-009-0473-1

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