“EPO activates 4 major signaling pathways: STAT5-activated transcription, PI3K-AKT, RAS-RAF-ERK, and PLC-PKC. EPO and EPOR in the neurovascular system act via Akt, Wnt1, mTOR, SIRT1, and FOXO proteins to prevent apoptotic cell injury (reviewed in Ostrowski and Heinrich 2018, Maiese 2016) and EPO may have therapeutic value in the nervous system.”

“EPO-induced increase in Runx2, OCN and Osterix is mediated by the activation in the Wnt/β-catenin pathway induced by EPO. Accordingly, EPO enhance mineralized nodule formation in PDLSCs, as EPO showed an increase of calcium deposits in a dose-dependent manner. Although CyclinD1 is upregulated by EPO, osteogenic differentiation primarily is mediated through Wnt/β-catenin signaling.” https://pmc.ncbi.nlm.nih.gov/articles/PMC6666380/

“Derivates of EPO gain more recognition due to its value in research, including three types of EPO derivatives that have been generated to lack erythropoietic activity yet retain neuroprotective effects: asialoerythropoietin, carbamylated EPO, and MEPO.” “Moreover, amino acid mutation of EPOs, such as S104I-EPO, activates the same survival signaling pathways as wild-type EPO. S104I-EPO activates the phosphorylation of AKT, ERK1/2, and STAT5 in primary neuronal cultures.”

“Methods to enable BBB penetration include fusion of the 166 amino acid EPO to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (mAb) against the transferrin receptor (TfR), and this new fusion protein is designated cTfRMAb-EPO. The high level of brain uptake of the fusion protein enables pharmacologic increases in exogenous EPO.”

“Epo-bp is the first purified human Epo receptor protein that has a specific ligand-binding affinity. The new products developed: human Epo-receptor cDNA PCR inserted recombinant vector, pJYL26, and anti-Epo-bp antibodies (α Epo-bp) may help to elucidate Epo-receptor structures and the mechanisms for the interactions of Epo-Epo receptor ligand binding, as well as progenitor cell differentiation and proliferation. They may also prove useful as clinical tools for differential diagnosis.”

“In humans, Epo enhanced immunoglobulin(Ig) production/proliferation (IgG, IgM, and IgA) and thymidine uptake by PCA-1 plasma cells generated in vitro.” “Although ineffective for models of unstimulated small resting B cells, results indicate that Epo could directly stimulate activated and differentiated B cells and could enhance B cell immunoglobulin production and proliferation.”

“Wnt1 enhanced cellular growth via a PKC pathway that increases STAT3 serine phosphorylation and activation. Stat3 stimulates the transcriptional activity of all four steroid hormone receptors(SHR) tested, AR, GR, PR and ER, in a hormone-dependent manner.” “Steroids regulate ion channels through Sigma-1 receptor actions.” Consideration into exploring interventions disregarding cancer shares similar limitations, given the PKC family represents a challenging target for anticancer therapy. “Evidently, one of the major problems found comprises the coexistence of several PKC isozymes known to exert overlapping, different, and even opposite biological functions in the same cell system, particularly within the context of Wnt signaling regulation in CC cell lines.”

“Sig-1R regulates the functional properties and the expression of some sodium, calcium, potassium, and TRP ion channels in the presence of steroids and the physiological consequences of these interplays at the cellular level are also discussed.” “Sigma-1 receptor oligomerization is disrupted by mutations in the GXXXG motif corresponding to amino acid residues 87–91. Mutations in the GXXXG decrease Sigma-1 Expression.” “Mutations were introduced into a putative membranous dimerization motif GxxxG of subunit e. We demonstrate that such a motif is involved in both the edification of supramolecular ATP synthase species and in correct mitochondrial morphology. In yeast, subunit e is involved in the dimerization/oligomerization of ATP synthases, probably in association with subunit g.” “Our data show for the first time that σ1 activation leads to enhancement of glycolysis and subsequent glycolytic ATP production, which are tightly linked to enhancing endothelial barrier function. In contrast, σ1 deficiency leads to disruption of the barrier function.”

“Interestingly, the negative roles of Sig-1R ligands on Cav channels have been observed in primary neuronal cultures from the hippocampus, where SA4503 (a Sig-1R agonist), inhibits N- and L-Type currents, producing an increase in axonal outgrowth.”

“Regulation of NMDAr by Sig-1R ligands has been extensively reported and, positive effects on their function, strongly correlate to Sig-1R’s activation. In addition, it has also been shown that the NR2 subunit of NMDAr is positively regulated by Sig-1R agonists, producing an upregulation in NR2-protein-expression and increasing traffic of NR2 to the plasma membrane. To take in consideration, NR1 upregulation as a consequence of Sigma-1 activation contributes to neuron over-excitability and pain.”

“Thus, from these studies and those discussed here, it is evident that a mechanism by which we may regulate ion channel physiology is through tools that allow us to manipulate the interactions between Sig-1R and these other proteins if this was to be possible without other severe consequences. But utmost important is that, by studying the interactions of Sig-1R with ion channels, we have gained valuable knowledge on how this receptor regulates ion channels. In turn, this has also helped us understand the physiological consequences of modifying the interplays between Sig-1R and ion channels for the function of the cells where these proteins are expressed.”

“EPO-induced increase in intracellular Ca2 in vascular smooth muscle and hematopoietic cells is due to extracellular Ca2 influx via a voltage-independent Ca2 conductance. Our studies provide a candidate pathway involving: 1.) EPO binding to EPO receptors, which leads to tyrosine phosphorylation of the -γ1 isoenzyme of PLC and membrane translocation of PLC-γ1, where it forms a complex with the EPO receptor itself. 2.) PLC-γ1-mediated hydrolysis of PIP2increases intracellular IP. 3.) Stimulation of Ca2 -activated 1pS Ca2 channels is initially triggered by intracellular Ca2 release from IP3-dependent stores and is sustained by extracellular Ca2 entry via the channel itself.”

“Sigma-1 Activation: The subsequent activation of protein kinase C beta1 and beta2 isoforms and the phosphorylation of a protein of the same molecular weight as the cloned sigma1 receptor lead to a desensitization of the sigma1 motor response. Our results indicate that the intracellular sigma1 receptor regulates several components implicated in plasma membrane-bound signal transduction. This might be an example of a mechanism by which an intracellular receptor modulates metabotropic responses.”

“The main function of Sig-1R is to regulate the Ca2 gradient between ER and mitochondria through the MAM(mitochondrion-associated endoplasmic reticulum membrane)”

“Sigma-1 receptor (sigma-1R) agonists enhance inositol 1,4,5-trisphosphate (IP3)-dependent calcium release from endoplasmic reticulum by inducing dissociation of ankyrin B 220 (ANK 220) from the IP3 receptor (IP3R-3), releasing it from inhibition.” “The mechanism by which sigma-1 receptors enhance ER calcium release upon co-stimulation of cells with Bradykinin(BDK) and a sigma-1 agonist has been shown to involve protein-protein interactions between the sigma-1 receptor, ankyrin isoforms, and the IP3receptor.”

“It should be noted that in the presence of extracellular calcium, 50 μm ATP produced a large rise in [Ca2 ]i that showed little difference across the various cell lines (data not shown). This observation suggests that in addition to P2Y2 receptors, these cells may also contain P2X receptors (ATP-gated calcium channels) or that P2Y2 receptor activation can subsequently stimulate extracellular calcium entry through channels. In any case, this extracellular component of the rise in [Ca2 ]i did not appear to be differentially regulated by sigma-1 receptors, lending specificity of the effect for intracellular calcium release.”

“It would be interesting to know more clearly how S1R associates with various proteins located in the ER lumen, ER membrane, cytoplasm and plasma membrane and to resolve the conflicting models of S1R topology and orientation. Given the topology model proposed by Mavylutov et al. (2018), the bulk of S1R may face the ER lumen. This topology is consistent with the well-described interaction of S1R with binding immunoglobulin protein(BiP), but raises it questions about how S1R interacts with proteins in the cytosol with only a small cytosolic N-terminal tail. Perhaps S1R has two or more structural elements or configurations responsible for the binding of S1R to different proteins. The structural and biological mechanisms of such interactions remain to be fully elucidated.”

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