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

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 alpha and beta-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 NRG1 beta significantly increased the transcript and protein level of the nAChR alpha 3 and beta 4 subunits. Consistent with these molecular data, nicotinic currents (IACh) were significantly up-regulated in NRG1 beta-treated sympathetic and parasympathetic MPG neurons. In contrast, the type III NRG1 and the a form of the NRG1 failed to alter the IACh. Inhibition of the ErbB2 tyrosine kinase completely abolished the effects of NRG1 beta on the IACh. Stimulation of the ErbB receptors by NRG1 beta 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 NRG1 beta-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.