Neuregulin 1 up‐regulates the expression of nicotinic acetylcholine receptors through the ErbB2/ErbB3‐PI3K‐MAPK signaling cascade in adult autonomic ganglion neurons

Abstract

We investigated effects of Neuregulin 1 (NRG1) on the expression of nicotinic acetylcholine receptor (nAChR) in major pelvic ganglion (MPG) from adult rat. MPG neurons were found to express transcripts for type I and III NRG1s as well as α and β-type epidermal growth factor (EGF)-like domains. Of the four ErbB receptor isoforms, ErbB1, ErbB2, and ErbB3 were expressed in MPG neurons. Treating MPG with NRG1β significantly increased the transcript and protein level of the nAChR α3 and β4 subunits. Consistent with these molecular data, nicotinic currents (I(ACh) ) were significantly up-regulated in NRG1β-treated sympathetic and parasympathetic MPG neurons. In contrast, the type III NRG1 and the α form of the NRG1 failed to alter the I(ACh) . Inhibition of the ErbB2 tyrosine kinase completely abolished the effects of NRG1β on the I(ACh) . Stimulation of the ErbB receptors by NRG1β activated the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). Immunoblot analysis revealed that PI3K-mediated activation of Akt preceded Erk1/2 activation in NRG1β-treated MPG neurons. Furthermore, specific PI3K inhibitors abrogated the phosphorylation of Erk1/2, while inhibition of MEK did not prevent the phosphorylation of Akt. Taken together, these findings suggest that NRG1 up-regulates nAChR expression via the ErbB2/ErbB3-PI3K-MAPK signaling cascade and may be involved in maintaining the ACh-mediated synaptic transmission in adult autonomic ganglia.

Ulinastatin inhibited sepsis‐induced spinal inflammation to alleviate peripheral neuromuscular dysfunction in an experimental rat model of neuromyopathy

“…These results were similar to those of our previous studies Xie et al 2016). In addition, NRG-1 could bind to muscle cell membrane receptors (ErbB2) to form a complex that phosphorylated the Ras protein, which further activated the MAP kinase signaling pathway, and activated the transcription and expression of ɛ-nAChR (Kim et al 2013). However, under some pathological states (such as burns, denervation, and sepsis), the expression of cand a7-nAChR were increased because of the decreased secretion of NRG-1.…”

Bladder outlet obstruction causes up-regulation of nicotinic acetylcholine receptors in bladder-projecting pelvic ganglion neurons

“…Alternatively, chronic administration of NGF antibody into the bladder could be considered. In addition to NGF, a potential mediator of functional plasticity is neuregulin 1, which was found to upregulate nAChR activity through a genomic mechanism in PG neurons (Kim et al, 2013). In our preliminary experiments , NGF stimulated the release of endogenous NRG1 from PG, suggesting an indirect action of NGF on the regulation of nAChR in PG neurons.…”

“…4). Secondly, in vitro short-term (6 h) treatment of dissociated PG neurons with NGF failed to alter nAChR expression (Kim et al, 2013). Interestingly, other trophic factors, including ciliary neurotrophic factor, exert no effects on nAChR expression in parasympathetic PG neurons.…”

“…Expression of nAChR subunits was quantified using a real-time PCR as previously described (Huang et al, 2004;Kim et al, 2013). Total RNA was extracted from whole ganglia using the RNeasy plus Kit (Qiagen, Valencia, CA, USA) according to the manufacturer's protocol.…”

Study of the Gastrointestinal Heat Retention Syndrome in Children: From Diagnostic Model to Biological Basis

“…PI3K-AKT and MAPK are two obvious enrichment pathways, and both of them are involved in cell proliferation, differentiation, and metabolic processes with a cross talk relation [41,42]. e other multiple pathways enriched are closely related to the PI3-AKT and MAKP pathway networks, such as estrogen receptor (ER) and ErbB mediating PI3-AKT, MAPK pathways [43,44], FoxO acting as a downstream target of PI3-AKT [45], and ras and rap1 activating the MAPK system [42]. Above all, we focused on the estrogen signaling pathway.…”