Abstract
A wide variety of peptides not only interact with the cell surface, but govern complex signaling from inside the cell. This has been referred to as an “intracrine” action, and the orchestrating molecules as “intracrines”. Here, we review the intracrine action of dynorphin B, a bioactive end-product of the prodynorphin gene, on nuclear opioid receptors and nuclear protein kinase C signaling to stimulate the transcription of a gene program of cardiogenesis. The ability of intracrine dynorphin B to prime the transcription of its own coding gene in isolated nuclei is discussed as a feed-forward loop of gene expression amplification and synchronization. We describe the role of hyaluronan mixed esters of butyric and retinoic acids as synthetic intracrines, controlling prodynorphin gene expression, cardiogenesis, and cardiac repair. We also discuss the increase in prodynorphin gene transcription and intracellular dynorphin B afforded by electromagnetic fields in stem cells, as a mechanism of cardiogenic signaling and enhancement in the yield of stem cell-derived cardiomyocytes. We underline the possibility of using the diffusive features of physical energies to modulate intracrinergic systems without the needs of viral vector-mediated gene transfer technologies, and prompt the exploration of this hypothesis in the near future.
Highlights
Cell-to-cell communication is usually viewed as a signaling cross-talk between neighboring cells, referred to as paracrine communication, or as a modality in which a given cell is able to release signaling molecules that in turn bind receptors on that same cell, according to a so-called autocrine communication.In 1984, Re and Coworkers introduced the term intracrine, to define a peptide action within the cell interiors, identifying a different route as compared to a peptide/hormone acting at the level of cell-surface receptors [1,2]
The findings reported here show the participation of dynorphin-mediated intracrine positive feedback loops in the differentiation of stem cells along a cardiac lineage and further suggest that dynorphin signaling interacts with targeted transcription factors, possibly through the upregulation of other intracrine loops
Feed-forward mechanisms are executed through the ability of dynorphin B of acting on its coupled receptor and signaling in isolated nuclei to stimulate the transcription of its own coding gene, as well as the transcription of homeodomain and zinc-finger transcription factors
Summary
Cell-to-cell communication is usually viewed as a signaling cross-talk between neighboring cells, referred to as paracrine communication, or as a modality in which a given cell is able to release signaling molecules that in turn bind receptors on that same cell, according to a so-called autocrine communication. A compelling evidence for a major role of an endorphinergic system in cardiogenesis was provided by a number of interrelated findings showing that: (1) Endogenous dynorphin B was essential in the cardiogenic process of GTR1 ESCs, a derivative of mouse R1 ES cells bearing the puromycin resistance gene driven by the cardiomyocyte-specific α-MHC promoter [60]; (2) immunoreactive dynorphin B was faintly detected in undifferentiated ESCs, while being highly enhanced inside ESC-derived cardiomyocytes, gathering around the nucleus [61]; (3) κ-specific opioid binding sites, besides being expressed on ESC plasma membranes [60], could be identified in ESC nuclei, with a single dissociation constant in the low-nanomolar range [61]; (4) a significant increase in the maximal binding capacity (Bmax) for a selective κ-opioid receptor ligand was detected in nuclei that had been isolated from ESC-derived cardiomyocytes, compared with nuclei from undifferentiated cells [61] On this basis, we were further encouraged to understand whether the presence of nuclear endorphin receptors in ESCs may have represented the interface for a causative intracrine patterning in cardiogenesis. Whether the intracellular hyaluronan signaling may encompass the deployment of intracrine endorphinergic paths remains to be established, and it is the subject for our ongoing investigation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
