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  • As many of the above

    2022-05-26

    As many of the above studies highlight, several decades of research on Cx43 has revealed that many of these functional roles are attributed to the C-terminal domain (CT) of this protein which cannot be explained by the formation and existence of intercellular channels. Recent findings on the existence of endogenous internally translated C-terminal isoforms from Cx43 mRNA [57], [58], [59], [60], which can explain general cytoplasmic activity of the proteins, are opening a new understanding of the regulation of gap junction trafficking and function. Roles previously assigned to full length Cx43 may in fact be due to the smaller isoforms instead.
    The Cx43 trafficking life cycle
    Alternative translation initiation sites within Cx43 Alternative translation has not been extensively studied in eukaryotic systems, but seems to be a source of considerable biologic diversity. Less than 20,000 gssg synthesis encode more than 80,000 protein-coding transcripts and a rough estimation of the number of proteins synthesized from these transcripts is in the range of 250,000 to 1 million in mammalian species. This suggests a substantial regulation at the transcriptional, post-transcriptional, and translational level [133]. In support of this, a recent study confirmed that there is no strong correlation between transcript and protein levels in mammals [134]. Indeed, the use of pre-existing mRNAs through regulation of translation is beneficial in many circumstances, because mRNA biogenesis is time consuming, whereas synthesis of protein is a fast process for many genes (including ion channels). Therefore, translational control plays an important role in a key biological processes. Translation defines not only the amount of protein produced, but ribosomal translation can be initiated from downstream AUG start sites by activation of alternative, internal AUG start codons. As a result distinct proteins can be generated from a single mRNA molecule (Fig. 2) [135]. Translation is initiated on most mRNAs by a canonical cap-dependent mechanism which involves binding of 10–13 different eukaryotic initiation factors (eIFs) at the mRNA 5′-UTR. Once recruited to the ribosomes, this initiation complex starts to scan the transcript from the 5′-UTR to locate the AUG start codon with a specific nucleotide context (Kozak sequence) thereby initiating translation [136]. However, several other non-canonical mechanisms were recently described [137]. An internal ribosome entry site (IRES) in viral and some cellular mRNAs was identified in close proximity to AUG start sites. Non-canonical internal initiation is generally observed under stressful physiological conditions (such as starvation, hypoxia, inflammation, or apoptosis) when cap-dependent translation is diminished [137], [138]. Other non-IRES alternative mechanisms of translation have been proposed. They include either direct internal binding of initiation translation factor eIF4E to the coding site of mRNA, or a mechanism called leaky ribosomal scanning [137], [139]. In second case translation can be initiated at the first AUG start site, but it will fail if the Kozak consensus sequence context is not optimal enough to start translation [136], [140], [141]. Translation will then be initiated at the subsequent internal AUG start site. To date, cap-independent translation and leaky ribosomal scanning are thought to represent the two basic mechanisms explaining the existence of alternative translation.
    Concluding remarks It is highly likely that the internally translated GJA1-20k isoform is a protein-chaperone or “beta-subunit” that serves and autoregulates the full length Cx43 trafficking to the cell-cell border. Production of isoforms and trafficking are tightly regulated and also directly involved in cytoskeleton based trafficking. Since EB1-tipped microtubules and actin are both impaired in stressed myocardium [39], [109], GJA1-20k could stabilize the cytoskeleton delivery apparatus during the injury or cell stress. Further understanding of the role of GJA1-20k in cytoskeleton-based vesicular transport may lead to introducing new therapeutic drugs such as mTOR inhibitors or others for preserving the abundance of Cx43 and regulating cell coupling at the intercalated disc.