PMID- 33434621 OWN - NLM STAT- MEDLINE DCOM- 20211224 LR - 20211224 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 165 DP - 2021 Mar TI - ERRgamma ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype. PG - 105423 LID - S1043-6618(21)00006-2 [pii] LID - 10.1016/j.phrs.2021.105423 [doi] AB - Brain derived neurotrophic factor (BDNF) promotes maturation of dopaminergic (DAergic) neurons in the midbrain and positively regulates their maintenance and outgrowth. Therefore, understanding the mechanisms regulating the BDNF signaling pathway in DAergic neurons may help discover potential therapeutic strategies for neuropsychological disorders associated with dysregulation of DAergic neurotransmission. Because estrogen-related receptor gamma (ERRgamma) is highly expressed in both the fetal nervous system and adult brains during DAergic neuronal differentiation, and it is involved in regulating the DAergic neuronal phenotype, we asked in this study whether ERRgamma ligand regulates BDNF signaling and subsequent DAergic neuronal phenotype. Based on the X-ray crystal structures of the ligand binding domain of ERRgamma, we designed and synthesized the ERRgamma agonist, (E)-4-hydroxy-N'-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2) (K(d) value, 8.35 mumol/L). HPB2 increased BDNF mRNA and protein levels, and enhanced the expression of the BDNF receptor tropomyosin receptor kinase B (TrkB) in human neuroblastoma SH-SY5Y, differentiated Lund human mesencephalic (LUHMES) cells, and primary ventral mesencephalic (VM) neurons. HPB2-induced upregulation of BDNF was attenuated by GSK5182, an antagonist of ERRgamma, and siRNA-mediated ERRgamma silencing. HPB2-induced activation of extracellular-signal-regulated kinase (ERK) and phosphorylation of cAMP-response element binding protein (CREB) was responsible for BDNF upregulation in SH-SY5Y cells. HPB2 enhanced the DAergic neuronal phenotype, namely upregulation of tyrosine hydroxylase (TH) and DA transporter (DAT) with neurite outgrowth, both in SH-SY5Y and primary VM neurons, which was interfered by the inhibition of BDNF-TrkB signaling, ERRgamma knockdown, or blockade of ERK activation. HPB2 also upregulated BDNF and TH in the striatum and induced neurite elongation in the substantia nigra of mice brain. In conclusion, ERRgamma activation regulated BDNF expression and the subsequent DAergic neuronal phenotype in neuronal cells. Our results might provide new insights into the mechanism underlying the regulation of BDNF expression, leading to novel therapeutic strategies for neuropsychological disorders associated with DAergic dysregulation. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Kim, Hyo In AU - Kim HI AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. FAU - Lee, Seungbeom AU - Lee S AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. FAU - Lim, Juhee AU - Lim J AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea; College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do 55338, Republic of Korea. FAU - Chung, Sungkyun AU - Chung S AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. FAU - Koo, Tae-Sung AU - Koo TS AD - Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea. FAU - Ji, Yu-Geun AU - Ji YG AD - Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea. FAU - Suh, Young-Ger AU - Suh YG AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. FAU - Son, Woo Sung AU - Son WS AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. Electronic address: wson@chamc.co.kr. FAU - Kim, Seok-Ho AU - Kim SH AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. Electronic address: ksh3410@cha.ac.kr. FAU - Choi, Hyun Jin AU - Choi HJ AD - College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, Republic of Korea. Electronic address: hjchoi3@cha.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210109 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (ESRRG protein, human) RN - 0 (Estradiol Congeners) RN - 0 (Ligands) RN - 0 (Membrane Glycoproteins) RN - 0 (Receptors, Estrogen) RN - 7171WSG8A2 (BDNF protein, human) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*biosynthesis/chemistry MH - Cell Line, Tumor MH - Dopaminergic Neurons/drug effects/*metabolism MH - Estradiol Congeners/chemistry/*pharmacology MH - Female MH - Humans MH - Ligands MH - Male MH - Membrane Glycoproteins/*biosynthesis/chemistry MH - Mice MH - Mice, Inbred C57BL MH - Microsomes, Liver/drug effects/metabolism MH - Phenotype MH - Pregnancy MH - Protein Structure, Secondary MH - Protein Structure, Tertiary MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, trkB/*biosynthesis/chemistry MH - Receptors, Estrogen/chemistry/*metabolism MH - Up-Regulation/drug effects/*physiology OTO - NOTNLM OT - ANA-12 (PubChem CID: 29799722) OT - BDNF OT - Dopaminergic neuron OT - ERRgamma OT - GSK4716 (PubChem CID: 5331325) OT - GSK5182 (PubChem CID: 6852176) OT - HPB2 OT - PD98059 (PubChem CID: 4713) OT - Parkinson's disease OT - SB203580 (PubChem CID: 176155) OT - SP600125 (PubChem CID: 8515) EDAT- 2021/01/13 06:00 MHDA- 2021/12/25 06:00 CRDT- 2021/01/12 20:08 PHST- 2020/09/17 00:00 [received] PHST- 2020/11/24 00:00 [revised] PHST- 2020/12/31 00:00 [accepted] PHST- 2021/01/13 06:00 [pubmed] PHST- 2021/12/25 06:00 [medline] PHST- 2021/01/12 20:08 [entrez] AID - S1043-6618(21)00006-2 [pii] AID - 10.1016/j.phrs.2021.105423 [doi] PST - ppublish SO - Pharmacol Res. 2021 Mar;165:105423. doi: 10.1016/j.phrs.2021.105423. Epub 2021 Jan 9.