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

Authors

  • Han-Gyu Kim,

    1. Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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  • Choong-Ku Lee,

    1. Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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  • Sung-Min Cho,

    1. Department of Neurosurgery, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
    2. The Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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  • Kum Whang,

    1. Department of Neurosurgery, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
    2. The Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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  • Byong-Ho Cha,

    1. Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
    2. The Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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  • Ju-Hyun Shin,

    1. Department of Urology, Chungnam National University Hospital, Daejeon, Republic of Korea
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  • Ki-Hak Song,

    1. Department of Urology, Chungnam National University Hospital, Daejeon, Republic of Korea
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  • Seong-Woo Jeong

    Corresponding author
    1. The Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
    • Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Address correspondence and reprint requests to Seong-Woo Jeong, Medical Building Rm 418, Ilsan-Dong 162, Wonju, Gangwon-do 220-701, Republic of Korea. E-mail: swjeong@yonsei.ac.kr

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 (IACh) 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 IACh. Inhibition of the ErbB2 tyrosine kinase completely abolished the effects of NRG1β on the IACh. 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.

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