Kappa opioid receptor contributes to EGF-stimulated neurite extension in development

Abstract

Epidermal growth factor (EGF), a mitogen, also stimulates neurite extension during development, but the underlying mechanism is elusive. This study reveals a functional role for kappa opioid receptor (KOR) in EGF-stimulated neurite extension, and the underlying mechanism. EGF and activated EGF receptor (EGFR) levels are elevated in embryonic spinal cords during late gestation stages, with concurrent rise in protein levels of KOR and axon extension markers, growth-associated protein 43 (GAP43), and transient axonal glycoprotein-1 (TAG-1). Both GAP43 and TAG-1 levels are significantly lower in KOR-null (KOR −/− ) spinal cords, and EGFR inhibitors effectively reduce the levels of KOR, GAP43, and TAG-1 in wildtype embryonic spinal cords. For KOR −/− or KOR-knockdown dorsal root ganglion (DRG) neurons, EGF can no longer effectively stimulate axon extension, which can be rescued by introducing a constitutive KOR expressing vector but not by a regulated KOR vector carrying its 5′ untranslated region, which can be bound and repressed by growth factor receptor-bound protein 7 (Grb7). Furthermore, blocking KOR activation by application of anti-dynorphin, KOR antagonist, or EGFR inhibitor effectively reduces axon extension of DRG neurons. Thus, EGF-stimulated axon extension during development is mediated, at least partially, by specific elevation of KOR protein production at posttranscriptional level, as well as activation of KOR signaling. The result also reveals an action of EGF to augment posttranscriptional regulation of certain mRNAs during developmental stages.5′ untranslated region | dorsal root ganglion | epidermal growth factor | growth factor receptor-bound protein 7 | posttranscriptional regulation

Sulf1 and Sulf2 expression in the nervous system and its role in limiting neurite outgrowth in vitro

“…However, another striking observation was that the same compounds that enhanced neurite outgrowth in the presence of CSPGs had also caused a small decline in neurite outgrowth in the absence of CSPGs. This can be explained by the fact that in the absence of molecules that inhibit axonal regeneration, both ErbB1 and HSPGs have been known to act as hubs for growth factor signalling (Chernoff, 1988;Goldshmit et al, 2004;Kim et al, 2003;Tsai et al, 2010). Hence, blockade of both these signalling molecules may result in delay or decline of growth related processes.…”

Platelet-Rich Plasma Promotes Axon Regeneration, Wound Healing, and Pain Reduction: Fact or Fiction

“…EGF is a family of proteins that includes neuregulins, which when administered to nerve trauma sites promotes axon regeneration [288][289][290][291], the development of larger diameter axons, and enhanced neurological recovery [288]. EGF further promotes axon regeneration and neurological recovery by inducing Schwann cell proliferation [292,293] and their release of neurotrophic factors that promote axon regeneration [294], Schwann cell migration [292,295], Schwann cell myelination [293,296], and angiogenesis [149].…”

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

“…EGF stimulation results in SHP-2-mediated dephosphorylation of the growth factor receptor bound protein GRB7, recruitment of the HUR-exportin-1 complex and nuclear export of oprk1 mRNA in P19 cells and dorsal root ganglion neurons [136]. EGF and the axonal guidance cue netrin-1 also induce FAK-mediated phosphorylation of GRB7 and derepression of oprk1 mRNA translation in the cytoplasm [137][138][139]. Intriguingly, depolarization-induced, possibly COPB1 and HUR-mediated, axonal transport and local translation of mouse oprk1 transcripts in terminals have been demonstrated in these cell models [140][141][142].…”