Alternative Erythropoietin Receptors in the Nervous System

Abstract

In addition to its regulatory function in the formation of red blood cells (erythropoiesis) in vertebrates, Erythropoietin (Epo) contributes to beneficial functions in a variety of non-hematopoietic tissues including the nervous system. Epo protects cells from apoptosis, reduces inflammatory responses and supports re-establishment of compromised functions by stimulating proliferation, migration and differentiation to compensate for lost or injured cells. Similar neuroprotective and regenerative functions of Epo have been described in the nervous systems of both vertebrates and invertebrates, indicating that tissue-protective Epo-like signaling has evolved prior to its erythropoietic function in the vertebrate lineage. Epo mediates its erythropoietic function through a homodimeric Epo receptor (EpoR) that is also widely expressed in the nervous system. However, identification of neuroprotective but non-erythropoietic Epo splice variants and Epo derivatives indicated the existence of other types of Epo receptors. In this review, we summarize evidence for potential Epo receptors that might mediate Epo’s tissue-protective function in non-hematopoietic tissue, with focus on the nervous system. In particular, besides EpoR, we discuss three other potential neuroprotective Epo receptors: (1) a heteroreceptor consisting of EpoR and common beta receptor (βcR), (2) the Ephrin (Eph) B4 receptor and (3) the human orphan cytokine receptor-like factor 3 (CRLF3).

Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4

“…New neuroprotectants that have a therapeutic effect and cause no adverse effects are important for the treatment for patients with neurodegenerative diseases. Recently, a number of small molecules, including recombinant proteins such as neurotrophic factors, growth factors, erythropoietin, and anti-amyloid β antibody, have also been developed for neuroprotection [41][42][43]. However, their clinical applications are limited by the appearance of serious side effects such as cerebral vasculitis and stroke, poor bioavailability, and low bloodbrain barrier permeability [44].…”

Intervention with erythropoietin in sarcopenic patients with femoral intertrochanteric fracture and its potential effects on postoperative rehabilitation

“…10,11 Particularly, it was also found that EPO stimulates proliferation and differentiation of skeletal muscle myoblasts, suggesting that the skeletal muscle might act as one of its targets. 10,11 Particularly, it was also found that EPO stimulates proliferation and differentiation of skeletal muscle myoblasts, suggesting that the skeletal muscle might act as one of its targets.…”

“…Erythropoietin (EPO) is known to have a wide range of therapeutic effects, such as anti-apoptosis, anti-oxidation, anti-inflammation and maintenance of vascular structure, as well as normal function. 10,11 Particularly, it was also found that EPO stimulates proliferation and differentiation of skeletal muscle myoblasts, suggesting that the skeletal muscle might act as one of its targets. 12,13 EPO might promote pro-myoblast effects through the activation of the same signaling cascades in hematopoietic cells.…”

Erythropoietin as a Modulator of Pathology in a Toxicant Mouse Model of Parkinson’s Disease

“…It is now thought that EPO's tissue-protective effects may be mediated through a separate heterodimeric receptor, consisting of one EPO subunit and one beta-common receptor (βCR) subunit (Brines et al, 2004;. Still, no study to date has demonstrated the interaction of EPO with this EPOR:βCR heterodimer, though a recently published article featuring a series of in silico experiments demonstrated the physical possibility of such an interaction based on protein and receptor conformations (Ostrowski & Heinrich, 2018). These authors suggest there may be additional substrates for EPO that have yet to be identified, as the proposed tissue protective receptor is not found in all cells that appear to benefit from EPO stimulation (Ostrowski & Heinrich, 2018).…”

“…Still, no study to date has demonstrated the interaction of EPO with this EPOR:βCR heterodimer, though a recently published article featuring a series of in silico experiments demonstrated the physical possibility of such an interaction based on protein and receptor conformations (Ostrowski & Heinrich, 2018). These authors suggest there may be additional substrates for EPO that have yet to be identified, as the proposed tissue protective receptor is not found in all cells that appear to benefit from EPO stimulation (Ostrowski & Heinrich, 2018). Although the molecular mechanisms by which EPO exerts its tissue-protective effects remain under investigation, researchers have recently begun to evaluate EPO's therapeutic potential in combination therapies for ischemia, as EPO's neuroprotective properties are well-established ).…”