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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/H953    most recent 00520.2008v1 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 Google Scholar Articles by Quinlan, C. L. Articles by Garlid, K. D. PubMed PubMed Citation Articles by Quinlan, C. L. Articles by Garlid, K. D.

Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoK_ATP channels

¹Department of Biology, Portland State University, Portland, OR; ²Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH; and ³Institut National de la Santé et de la Recherche Médicale Unit 828, University Victor Segalen-Bordeaux 2, University Hospital of Bordeaux, Bordeaux, France

Submitted 15 May 2008 ; accepted in final form 6 July 2008

Perfusion of the heart with bradykinin triggers cellular signaling events that ultimately cause opening of mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels, increased H₂O₂ production, inhibition of the mitochondrial permeability transition (MPT), and cardioprotection. We hypothesized that the interaction of bradykinin with its receptor induces the assembly of a caveolar signaling platform (signalosome) that contains the enzymes of the signaling pathway and that migrates to mitochondria to induce mitoK_ATP channel opening. We developed a novel method for isolating and purifying signalosomes from Langendorff-perfused rat hearts treated with bradykinin. Fractions containing the signalosomes were found to open mitoK_ATP channels in mitochondria isolated from untreated hearts via the activation of mitochondrial PKC-. mitoK_ATP channel opening required signalosome-dependent phosphorylation of an outer membrane protein. Immunodetection analysis revealed the presence of the bradykinin B₂ receptor only in the fraction isolated from bradykinin-treated hearts. Immunodetection and immunogold labeling of caveolin-3, as well as sensitivity to cholesterol depletion and resistance to Triton X-100, attested to the caveolar nature of the signalosomes. Ischemic preconditioning, ischemic postconditioning, and perfusion with ouabain also led to active signalosome fractions that opened mitoK_ATP channels in mitochondria from untreated hearts. These results provide initial support for a novel mechanism for signal transmission from a plasma membrane receptor to mitoK_ATP channels.

bradykinin; mitochondria; cardioprotection; protein kinase C; ouabain