PMID- 29355947 OWN - NLM STAT- Publisher LR - 20240227 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) DP - 2018 Jan 22 TI - Corticotropin-releasing hormone-binding protein is up-regulated by brain-derived neurotrophic factor and is secreted in an activity-dependent manner in rat cerebral cortical neurons. LID - 10.1111/jnc.14310 [doi] AB - A recent study revealed that corticotropin-releasing hormone (CRH) in the cerebral cortex (CTX) plays a regulatory role in emotional behaviors in rodents. Given the functional interaction between brain-derived neurotrophic factor (BDNF) and the CRH-signaling pathway in the hypothalamic-pituitary-adrenal axis, we hypothesized that BDNF may regulate gene expression of CRH and its related molecules in the CTX. Findings of real-time quantitative PCR (RT-qPCR) indicated that stimulation of cultured rat cortical neurons with BDNF led to marked elevations in the mRNA levels of CRH and CRH-binding protein (CRH-BP). The BDNF-induced up-regulation of CRH-BP mRNA was attenuated by inhibitors of tropomyosin related kinase (Trk) and MEK, but not by an inhibitor for PI3K and Phospholipase C gamma (PLCgamma). The up-regulation was partially blocked by an inhibitor of lysine-specific demethylase (KDM) 6B. Fluorescent imaging identified the vesicular pattern of pH-sensitive green fluorescent protein-fused CRH-BP (CRH-BP-pHluorin), which co-localized with mCherry-tagged BDNF in cortical neurons. In addition, live-cell imaging detected drastic increases of pHluorin fluorescence in neurites upon membrane depolarization. Finally, we confirmed that tetrodotoxin partially attenuated the BDNF-induced up-regulation of CRH-BP mRNA, but not that of the protein. These observations indicate the following: In cortical neurons, BDNF led to gene expression of CRH-BP and CRH. TrkB, MEK, presumably ERK, and KDM6B are involved in the BDNF-induced gene expression of CRH-BP, and BDNF is able to induce the up-regulation in a neuronal activity-independent manner. It is suggested that CRH-BP is stored into BDNF-containing secretory granules in cortical neurons, and is secreted in response to membrane depolarization. CI - (c) 2018 International Society for Neurochemistry. FAU - Adachi, Naoki AU - Adachi N AD - Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda, Japan. FAU - Suzuki, Shingo AU - Suzuki S AUID- ORCID: 0000-0003-3878-1909 AD - Faculty of Medicine, Department of Anatomy and Neurobiology, Kagawa University, Kagawa, Japan. FAU - Matsuoka, Hidetada AU - Matsuoka H AD - School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. FAU - Fushimi, Satoko AU - Fushimi S AD - Faculty of Medicine, Department of Anesthesiology, Kagawa University, Kagawa, Japan. FAU - Ono, Junichiro AU - Ono J AD - Faculty of Medicine, Department of Anesthesiology, Kagawa University, Kagawa, Japan. FAU - Ohta, Ken-Ichi AU - Ohta KI AUID- ORCID: 0000-0002-2929-6154 AD - Faculty of Medicine, Department of Anatomy and Neurobiology, Kagawa University, Kagawa, Japan. FAU - Hirai, Yohei AU - Hirai Y AD - Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda, Japan. FAU - Miki, Takanori AU - Miki T AD - Faculty of Medicine, Department of Anatomy and Neurobiology, Kagawa University, Kagawa, Japan. FAU - Koshimizu, Hisatsugu AU - Koshimizu H AUID- ORCID: 0000-0002-8619-6678 AD - Japan, Society for the Promotion of Science (JSPS), Tokyo, Japan. AD - Bio-interface Research Group, Health Research Inst., National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Japan. AD - Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan. LA - eng PT - Journal Article DEP - 20180122 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R OTO - NOTNLM OT - BDNF OT - CRH OT - CRH-BP OT - TrkB OT - cerebral cortical neurons EDAT- 2018/01/23 06:00 MHDA- 2018/01/23 06:00 CRDT- 2018/01/23 06:00 PHST- 2017/08/04 00:00 [received] PHST- 2017/12/19 00:00 [revised] PHST- 2018/01/09 00:00 [accepted] PHST- 2018/01/23 06:00 [pubmed] PHST- 2018/01/23 06:00 [medline] PHST- 2018/01/23 06:00 [entrez] AID - 10.1111/jnc.14310 [doi] PST - aheadofprint SO - J Neurochem. 2018 Jan 22. doi: 10.1111/jnc.14310.