Connexins are protein subunits that constitute the gap junction channel, a dodecameric channel connecting two neighbouring cells formed by two hexameric hemichannels provided by either cell. The gap junction channel permits intercellular communication by allowing the propagation of the action potential and the transfer of small molecules such as cAMP. Six different gap junctional proteins (connexins; Cx) have been identified in the cardiovascular system: Cx31. 9, Cx37, Cx40, Cx43, Cx45, Cx46, Cx50, and Cx57 (the molecular mass in kDa is given by the number)[1, 2]. In the heart, there are mainly three isoforms that differ in their molecular weight: connexin 43 (a 43-kDa connexin; Cx43), which is found in most parts of the heart; connexin 40 (Cx40), which is mainly expressed in atria and in the conduction system; and connexin 45 (Cx45), which is expressed predominantly in embryonic stages and has been identified in parts of the ventricular conduction system of mice and rats [3]. Moreover, Cx45 was shown to be expressed in co-cultures of neonatal rat cardiomyocytes with fibroblasts [4] and is involved in myocyte/fibroblast coupling in the sinoatrial node [5]. Cx50 has been found in valvular tissue of the rat heart [6]. Connexins have four transmembrane regions, one intracellular and two extracellular loops, and intracellular N-and C-terminal tails. The length of the C-terminus differs among the various isoforms and is subject to phosphorylation by a number of kinases (for review, see Ref.[2]). Connexins are synthesized in the rough endoplasmic reticulum, folded, and transported to the Golgi apparatus within vesicles. In the trans-Golgi network, connexins are oligomerized to hexameric connexons, which are transferred thereafter to the plasma membrane along microtubular structures. They dock to the connexon of the neighbouring cell via the extracellular loops of the connexins, thereby forming the complete dodecameric gap junction channel. The single channel conductance is regulated by C-terminal phosphorylation. These gap junction channels are subject to high turnover and are degraded via lysosomal and (mainly) proteasomal degradation. The half-life of Cx43 was determined to be on the order of 90 min [7]. It has been assumed that phosphorylation and ubiquitinylation are involved in initiation of this connexin degradation. Finally, besides their function in intercellular communication, the connexins, at least Cx43, may have a role as gene regulators: thus, the C-terminus of Cx43 localizes to the cell nucleus and can inhibit cell growth [8]. In the article by Boengler et al.[9](see this issue), the authors describe a new localization of connexins in cardiac tissue; they detected Cx43 in the mitochondia using a number of different, independent methods. Interestingly,> 80% of Cx43 found in the mitochondria was phosphorylated (as detected indirectly by higher molecular weight in Western blots, see Fig. 5A of Boengler et al.[9]). The amount of mitochondrial Cx43 was enhanced after two periods of 5-minute ischemic preconditioning in rat hearts, which means a rapid translocation of the protein that–taking into consideration a half-life time of about 90 min–cannot be explained by inhibition of degradation. Similarly, they found this increase in mitochondrial Cx43 in pig hearts subjected to ischemic preconditioning and low-flow ischemia, while ischemia itself did not seem to influence translocation. Electron microscopy showed the location of immunogoldlabelled anti-Cx43 antibody within the mitochondria (see Fig. 2B of Boengler et al.[9]), compatible with a localization near the inner mitochondrial membrane or the matrix.

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