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Iptakalim alleviates synaptic damages via targeting mitochondrial ATP‐sensitive potassium channel in depression
Author(s) -
Guo Wei,
Tang ZiYang,
Cai ZhenYu,
Zhao WenE,
Yang Jin,
Wang XiPeng,
Ji Juan,
Huang XinXin,
Sun XiuLan
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100124rr
Subject(s) - damages , potassium channel , atp sensitive potassium channel , chemistry , depression (economics) , pharmacology , microbiology and biotechnology , neuroscience , biophysics , medicine , biology , endocrinology , economics , glibenclamide , diabetes mellitus , macroeconomics , political science , law
Abstract Synaptic plasticity damages play a crucial role in the onset and development of depression, especially in the hippocampus, which is more susceptible to stress and the most frequently studied brain region in depression. And, mitochondria have a major function in executing the complex processes of neurotransmission and plasticity. We have previously demonstrated that Iptakalim (Ipt), a new ATP‐sensitive potassium (K‐ATP) channel opener, could improve the depressive‐like behavior in mice. But the underlying mechanisms are not well understood. The present study demonstrated that Ipt reversed depressive‐like phenotype in vivo (chronic mild stress‐induced mice model of depression) and in vitro (corticosterone‐induced cellular model). Further study showed that Ipt could upregulate the synaptic‐related proteins postsynaptic density 95 (PSD 95) and synaptophysin (SYN), and alleviated the synaptic structure damage. Moreover, Ipt could reverse the abnormal mitochondrial fission and fusion, as well as the reduced mitochondrial ATP production and collapse of mitochondrial membrane potential in depressive models. Knocking down the mitochondrial ATP‐sensitive potassium (Mito‐KATP) channel subunit MitoK partly blocked the above effects of Ipt. Therefore, our results reveal that Ipt can alleviate the abnormal mitochondrial dynamics and function depending on MitoK, contributing to improve synaptic plasticity and exert antidepressive effects. These findings provide a candidate compound and a novel target for antidepressive therapy.