ATP-sensitive potassium channels: uncovering novel targets for treating depression.
ATP-sensitive potassium (K-ATP) channels have been shown to couple membrane electrical activity to energy metabolism in a variety of cells and are important in several physiological systems. In the brain, K-ATP channels are strongly expressed in the neuronal circuitry. The distributional profile and functional significance of K-ATP channels suggest that they may be involved in stress-induced depression. First, we showed that chronic mild stress (CMS) significantly increased the expression of hippocampal Kir6.2 and Kir6.1 subunits of K-ATP channels. Next, using Kir6.2 knockout (Kir6.2(-/-)) mice, we presented that Kir6.2 deficiency resulted in antidepressant-like behaviors under non-stress conditions, but aggravated depressive behaviors accompanied by the loss of CA3 neuron and the reduction of brain-derived neurotrophic factor in hippocampus under chronic stress. Finally, we demonstrated that the K-ATP channel opener iptakalim, as well as a classical antidepressant fluoxetine, can reverse CMS-induced depression-related behaviors and counteract the deleterious effects of stress on hippocampus in wild-type mice, but only partially alleviate these symptoms in Kir6.2(-/-) mice. Collectively, our findings demonstrate that K-ATP channels are involved in the pathogenesis of depression and may be a promising target for the therapy of depression.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
Yi
Y
Fan
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
Hui
H
Kong
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
Xinhai
X
Ye
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
Jianhua
J
Ding
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China. ghu@njmu.edu.cn.|Biomedical Functional Materials Collaborative Innovation Center, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, Jiangsu, China. ghu@njmu.edu.cn.|Parkinson's Disease Center of Beijing Institute for Brain Disorders, 45 Changchun St., Beijing, 100053, China. ghu@njmu.edu.cn.|Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, Jiangsu, China. ghu@njmu.edu.cn.
Gang
G
Hu
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D010766:Phosphorylation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications; D000099161:Kcnj11 Channel
D019208:Brain-Derived Neurotrophic Factor; D003345:Corticosterone; D006897:Hydroxyindoleacetic Acid; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D012701:Serotonin; D000099161:Kcnj11 Channel; C092520:uK-ATP-1 potassium channel
Chronic mild stress; Depression; Iptakalim; K-ATP channel; Neurogenesis