Connexin 43 acts as a cytoprotective mediator of signal transduction by stimulating mitochondrial KATP channels in mouse cardiomyocytes
Authors: Gerd Heusch
Dennis Rottlaender
Kerstin Boengler
Jeannette Endres-Becker
Astrid Buechert
Martin Wolny
Astrid Schwaiger
Rainer Schulz
Lukas J Motloch
Uta C Hoppe
Guido Michels
Journal: Journal of Clinical Investigation (2010)
Discipline: CLINICAL MEDICINE
Keywords: Potassium channels; Mitochondrial ATP-sensitive K+ channels; PKC; Cytoprotection; Connexin 43
Affiliations: Department of Internal Medicine III, University of Cologne, Cologne, Germany.

Abstract:  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. 

Retracted: Yes

PubPeer comments:
 (a) The authors considered multiple criteria decision making with picture 2-Tuple linguistic information in this paper. The authors pointed out some deficiencies in Ref[17] and Ref[18] and proposed some new arithmetic operations and new aggregation operations on picture 2-Tuple linguistic numbers. However, the authors used the ranking method proposed in Ref[17] and Ref[18], which was not well justified and actually not well defined. The ranking method for picture 2-Tuple linguistic numbers is presented in Definition 7, Definition 8, and Theorem 1. The function $F(t)$ and $H(t)$ are defined in Definition 7 and Definition 8, respectively. A ranking method based on $F(t)$ and $H(t)$ is introduced in Theorem 1. Let $$(s_{epsilon}, vartheta) =(s_1,0)$$ $$(mu, eta,  u) =(0.5, 0, 0.5)$$ According to eq.(4), it follows that $$Delta^{-1}(s_1, 0) =1$$ $$frac{1+mu- u}{2} = 0.5$$ and $$Delta^{-1}(s_1, 0)cdot frac{1+mu- u}{2} = 0.5$$ However, according to eq.(3) of Definition 5, $$Delta: [1,g]to Stimes [-0.5, 0.5)$$ This means that $$F(t) = Delta(Delta^{-1}(s_1, 0)cdot frac{1+mu- u}{2}) =Delta(0.5)$$ is not defined. The situation for $H(t)$ defined by eq.(6) is similar by checking the above numerical example. As a result, the ranking method in Theorem is not well defined. Consequently, some results presented in the rest of this paper, e.g., Theorem 5, are not reliable because they rely on the ranking method defined in Theorem 1. (b) Besides, some claims in this paper are also not reliable. For example, the authors claimed in Theorem 3 and Theorem 4 that $t_1oplus t_2$ and $t_1otimes t_2$ are still picture 2-tuple linguistic numbers. However, according to Definition 4 and Definition 5, the linguistic term set for a picture 2-tuple linguistic number is fixed as $$S={s_{epsilon}| epsilon =1, 2, ldots, g}$$ It is clear that the operations $t_1oplus t_2$ and $t_1otimes t_2$ defined by Definition 9 and illustrated by Example 2 cannot guarantee that the resulted linguistic terms are still in the set $$S={s_{epsilon}| epsilon =1, 2, ldots, g}$$    ,