Connexin 43 acts as a cytoprotective mediator of signal transduction by stimulating mitochondrial KATP channels in mouse cardiomyocytes.
Potassium (K+) channels in the inner mitochondrial membrane influence cell function and survival. Increasing evidence indicates that multiple signaling pathways and pharmacological actions converge on mitochondrial ATP-sensitive K+ (mitoKATP) channels and PKC to confer cytoprotection against necrotic and apoptotic cell injury. However, the molecular structure of mitoKATP channels remains unresolved, and the mitochondrial phosphoprotein(s) that mediate cytoprotection by PKC remain to be determined. As mice deficient in the main sarcolemmal gap junction protein connexin 43 (Cx43) lack this cytoprotection, we set out to investigate a possible link among mitochondrial Cx43, mitoKATP channel function, and PKC activation. By patch-clamping the inner membrane of subsarcolemmal murine cardiac mitochondria, we found that genetic Cx43 deficiency, pharmacological connexin inhibition by carbenoxolone, and Cx43 blockade by the mimetic peptide 43GAP27 each substantially reduced diazoxide-mediated stimulation of mitoKATP channels. Suppression of mitochondrial Cx43 inhibited mitoKATP channel activation by PKC. MitoKATP channels of interfibrillar mitochondria, which do not contain any detectable Cx43, were insensitive to both PKC activation and diazoxide, further demonstrating the role of Cx43 in mitoKATP channel stimulation and the compartmentation of mitochondria in cell signaling. Our results define a role for mitochondrial Cx43 in protecting cardiac cells from death and provide a link between cytoprotective stimuli and mitoKATP channel opening, making Cx43 an attractive therapeutic target for protection against cell injury.
Rottlaender
Dennis
D
Department of Internal Medicine III, University of Cologne, Cologne, Germany.
Boengler
Kerstin
K
Wolny
Martin
M
Michels
Guido
G
Endres-Becker
Jeannette
J
Motloch
Lukas J
LJ
Schwaiger
Astrid
A
Buechert
Astrid
A
Schulz
Rainer
R
Heusch
Gerd
G
Hoppe
Uta C
UC
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D018031:Connexin 43 / Q000378:metabolism*; D019610:Cytoprotection; D006579:Heterozygote; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009336:Necrosis; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry; D015221:Potassium Channels / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction
D018031:Connexin 43; D010455:Peptides; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D011493:Protein Kinase C