Intracrine Endorphinergic Systems in Modulation of Myocardial Differentiation

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.

Keywords: cardiac regeneration; cardiogenesis; dynorphin B; electromagnetic fields; hyaluronan esters; intracrine; nuclear opioid receptors; prodynorphin gene; stem cells; transcription factors.

Figure 1

Intracrine patterning. The figure depicts a scheme of intracrine signaling within the context of intra- and extra-cellular communication via paracrine, autocrine, and exosomal routes. GA: Golgi Apparatus; RE: Endoplasmic Reticulum; PS: Perinuclear Space; red shape: receptor; blue shape: signal.

Figure 2

Intracrine dynorphin B pathway in rat ventricular cardiomyocytes. Th figure represents a virtual cell where different experimental evidence (detailed in the manuscript) is schematically shown. SR: Sarcoplasmic reticulum; Ins(1,3,4,5)P4: Inositol 1,3,4,5-tetrakisphosphate; Ins(1,4,5)P3: Inositol 1,4,5-trisphosphate; PKC: Protein kinase C.

Figure 3

Intracrine dynorphin B pathway in embryonic stem cells (ESCs). The figure represents a virtual ES cell where different experimental evidence (detailed in the manuscript) is shown. MHC: α-Myosin heavy chain; MLC: Myosin light chain; SA: α-sarcomeric actinin.