Gang Wu1,2, Xiu-Xiu Liu1,2, Nan-Nan Lu1, Qi-Bing Liu3, Yun Tian1, Wei-Feng Ye1, Guo-Jun Jiang4, Rong-Rong Tao1, Feng Han1, Ying-Mei Lu2. 1. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. 2. School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, China. 3. School of Pharmacy, Hainan Medical College, Haikou, China. 4. Department of Pharmacy, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang, China.
Abstract
AIMS: The receptor tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In this study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. RESULTS: Here, we show that the endothelial cell-specific deletion of ErbB4 induces decreased exploratory behavior in adult mice. However, the water maze task for spatial memory and the memory reconsolidation test reveal no changes; additionally, we observe no impairment in CaMKII phosphorylation in Cdh5Cre;ErbB4f/f mice, which indicates that the endothelial ErbB4 deficit leads to decreased exploratory activity rather than direct memory deficits. Furthermore, decreased brain metabolism, which was measured using micro-positron emission tomography, is observed in the Cdh5Cre;ErbB4f/f mice. Consistently, the immunoblot data demonstrate the downregulation of brain Glut1, phospho-ULK1 (Ser555), and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively, our findings suggest that endothelial ErbB4 plays a critical role in regulating brain function, at least in part, through maintaining normal brain energy homeostasis. CONCLUSIONS: Targeting ErbB4 or the modulation of endothelial ErbB4 signaling may represent a rational pharmacological approach to treat neurological disorders.
AIMS: The receptor tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In this study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. RESULTS: Here, we show that the endothelial cell-specific deletion of ErbB4 induces decreased exploratory behavior in adult mice. However, the water maze task for spatial memory and the memory reconsolidation test reveal no changes; additionally, we observe no impairment in CaMKII phosphorylation in Cdh5Cre;ErbB4f/f mice, which indicates that the endothelial ErbB4 deficit leads to decreased exploratory activity rather than direct memory deficits. Furthermore, decreased brain metabolism, which was measured using micro-positron emission tomography, is observed in the Cdh5Cre;ErbB4f/f mice. Consistently, the immunoblot data demonstrate the downregulation of brain Glut1, phospho-ULK1 (Ser555), and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively, our findings suggest that endothelial ErbB4 plays a critical role in regulating brain function, at least in part, through maintaining normal brain energy homeostasis. CONCLUSIONS: Targeting ErbB4 or the modulation of endothelial ErbB4 signaling may represent a rational pharmacological approach to treat neurological disorders.
Authors: Carles Cantó; Alexander V Chibalin; Brian R Barnes; Stephan Glund; Elisabet Suárez; Jeffrey W Ryder; Manuel Palacín; Juleen R Zierath; Antonio Zorzano; Anna Gumà Journal: J Biol Chem Date: 2006-06-01 Impact factor: 5.157
Authors: Thibaut Duparc; Damien Naslain; André Colom; Giulio G Muccioli; Nicolas Massaly; Nathalie M Delzenne; Philippe Valet; Patrice D Cani; Claude Knauf Journal: Antioxid Redox Signal Date: 2010-09-29 Impact factor: 8.401