Activation of glutamine synthetase(GS)as a new strategy for the treatment of major depressive disorder and other GS-related diseases  

作　　者：Jae Soon Kang Hwajin Kim Ji Hyeong Baek Miyoung Song Hyeongchan Park Wonjune Jeong Hye Jin Chung Dae Young Yoo Dong Kun Lee Sang Won Park Hyun Joon Kim 

机构地区：[1]Department of Anatomy and Convergence Medical Science,College of Medicine,Institute of Medical Science,Tyrosine Peptide Multiuse Research Group,Anti-aging Bio Cell Factory Regional Leading Research Center,Gyeongsang National University,Jinju,Gyeongnam,Republic of Korea [2]Department of Pharmacology and Convergence Medical Science,College of Medicine,Institute of Medical Science,Tyrosine Peptide Multiuse Research Group,Anti-aging Bio Cell Factory Regional Leading Research Center,Gyeongsang National University,Jinju,Gyeongnam,Republic of Korea [3]College of Pharmacy and Research Institute of Pharmaceutical Sciences,Gyeongsang National University,Jinju,Gyeongnam,Republic of Korea [4]Department of Anatomy and Cell Biology,College of Veterinary Medicine,Research Institute for Veterinary Science,Seoul National University,Seoul,Republic of Korea [5]Department of Physiology and Convergence Medical Sciences,College of Medicine,Institute of Medical Science,Tyrosine Peptide Multiuse Research Group,Gyeongsang National University,Jinju,Gyeongnam,Republic of Korea

出　　处：《Acta Pharmacologica Sinica》2025年第4期880-891,共12页中国药理学报(英文版)

基　　金：supported by the National Research Foundation(NRF)(Grant numbers NRF-2021R1A5A802949012 and 2022R1A2C100529611);the Commercializations Promotion Agency for R&D Outcomes(COMPA)(Grant number 1711173796)funded by the Ministry of Science and ICT(MSIT)of the Korean government.

摘　　要：Glutamine synthetase(GS)plays a crucial role in the homeostasis of the glutamate–glutamine cycle in the brain.Hypoactive GS causes depressive behaviors.Under chronic stress,GS has no change in expression,but its activity is decreased due to nitration of tyrosine(Tyr).Thus,we speculate that agents that prevent nitration or facilitate denitration of GS would be candidates for new antidepressants.Using human recombinant GS and mouse lysate from the medial prefrontal cortex,we demonstrated that Tyr(0.0313−0.5µM)dose-dependently protected GS activity against peroxynitrite-induced Tyr-nitration of GS.Diet supplementation with Tyr exerted significant antidepressant effects in a chronic immobilization stress depression mouse model.We further found that dipeptides,such as tyrosyl-glutamine(YQ),that had appropriate chemical properties for medication also increased GS activity both in vitro and in vivo and exerted antidepressant effects.Because reduced GS activity also occurs in epilepsy and hyperammonemia,we evaluated whether Tyr and YQ had therapeutic effects.Interestingly,Tyr or YQ administration significantly attenuated kainic acid-induced seizures in mice and reduced blood ammonia levels in azoxymethane-or bile duct ligation-induced hyperammonemia mouse models,which was accompanied by an increment in GS activity.The activation of GS was accomplished by a decrement in Tyr-nitration,so-called Tyr-denitration.Therefore,this study demonstrates that the activation of GS could be a new strategy to treat depression and other GS-related diseases.

关 键 词：depression glutamine synthetase tyrosine nitration tyrosine-containing dipeptide EPILEPSY HYPERAMMONEMIA 

分 类 号：R749.4[医药卫生—神经病学与精神病学]