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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/H396    most recent 00448.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Naitoh, K. Articles by Shimamoto, K. Search for Related Content PubMed PubMed Citation Articles by Naitoh, K. Articles by Shimamoto, K.

Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning

Second Department of Internal Medicine, Sapporo Medical University School of Medicine

Submitted 28 April 2008 ; accepted in final form 17 December 2008

Ischemic preconditioning (PC) suppresses chemical coupling of cardiomyocytes via gap junctions (GJs) during ischemia, which is an adjunct mechanism of protection. The aim of this study was to characterize roles of protein kinases in PC-induced GJ modulation. In isolated rat hearts, ventricular tissues were sampled before and after ischemia with or without PC, and intercalated disc-rich fractions were separated for immunoprecipitation and immunoblotting. Levels of protein kinase C (PKC)-, p38mitogen-activated protein kinase (MAPK)-, and Src coimmunoprecipitated with connexin-43 (Cx43) were increased after ischemia, whereas p38MAPKβ was not detected in the Cx43 immunoprecipitates. PC did not modify the level of Cx43-Src complex after ischemia. However, PC enhanced Cx43-PKC complex formation, which was abolished by PKC translocation inhibitory peptide (TIP). In contrast, PC reduced Cx43-p38MAPK complex level and p38MAPK activity in the Cx43 immunoprecipitates after ischemia. The effect of PC on Cx43-p38MAPK interaction was mimicked by SB-203580, a p38MAPK inhibitor. PC reduced permeability of GJs to Lucifer yellow in the myocardium at 25 min after ischemia, and this effect was abolished by PKC-TIP. SB-203580 increased the GJ permeability at 15 min after ischemia compared with that in untreated controls, but the difference became insignificant 25 min after ischemia. In conclusion, PC has distinct effects on interaction of GJ Cx43 with PKC, p38MAPK, and Src during ischemia. Suppression of GJ permeability during ischemia by PC is primarily achieved by enhanced interaction of Cx43 with PKC, which overwhelms the counterbalancing effect of reduced Cx43-p38MAPK interaction.

connexin-43; protein kinase C; p38 mitogen-activated protein kinase; Src