title: 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.
authors.affiliation: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Han-Gyu
authors.initials: HG
authors.lastname: Kim
authors.forename: Choong-Ku
authors.initials: CK
authors.lastname: Lee
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Cho
authors.forename: Kum
authors.initials: K
authors.lastname: Whang
authors.forename: Byong-Ho
authors.initials: BH
authors.lastname: Cha
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Shin
authors.forename: Ki-Hak
authors.initials: KH
authors.lastname: Song
authors.forename: Seong-Woo
authors.initials: SW
authors.lastname: Jeong
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005725:Ganglia, Autonomic / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000109:Acetylcholine; D003513:Cycloheximide; D004791:Enzyme Inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020890:Neuregulin-1; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011978:Receptors, Nicotinic; C490580:Nrg1 protein, rat