β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation
β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation
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β-羟基丁酸通过海马 CaMKII-α β-羟基丁酰化减少可卡因条件性位置偏好的恢复
DOI：
10.1016/j.celrep.2022.111724
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发表时间：
2022
期刊：
影响因子：
8.8
通讯作者：
Jingwei Tian
中科院分区：
文献类型：
--
作者：
Hongchun Li;Xuemei Wan;Zhixiang Wu;Yuanyi Zhou;Rong Chen;Wei Xu;Jiamei Zhang;Zhen Yang;Lin Bai;Jie Zhang;Feng Qin;Liang Wang;Yaxing Chen;Linhong Jiang;Yuman He;Xiaojie Wang;Qingfan Wei;Shu Li;Yanping Dai;Yuanyuan Chen;Yonghai Wang;Hongbo Wang;Jingwei Tian
研究表明生酮饮食（KD）对癫痫的治疗作用，但KD对药物恢复的影响在很大程度上是不清楚的。本研究旨在探讨KD消费是否具有治疗可卡因恢复的潜力及其分子机制。我们发现，KD显著降低了小鼠可卡因诱导的恢复，并伴随着海马中最丰富的酮体β-羟基丁酸酯（β-OHB）水平的显著升高。其潜在机制是β-OHB翻译后通过β-羟基丁基化修饰CaMKII-α，从而显著抑制T286自磷酸化，下调CaMKII活性。总之，我们的研究结果表明，β-羟基丁基化是CaMKII-α的翻译后修饰，在介导KD消耗减少可卡因恢复的作用中起关键作用。
Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of β-hydroxybutyrate (β-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that β-OHB posttranslationally modifies CaMKII-α with β-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that β-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.