Kir6.2, a pore-forming subunit of the ATP-sensitive potassium (KATP) channels, regulates the functions of metabolically active tissues and acts as an ideal therapeutic target for multiple diseases. Previous studies have been conducted on peripheral kir6.2, but its precise physiological roles in the central nervous system (CNS) have rarely been revealed. In the current study, we evaluated the neurophenotypes and neuroethology of kir6.2 knockout (kir6.2^−/−) mice. We demonstrated the beneficial effects of kir6.2 on maintaining the morphology of mesencephalic neurons and controlling the motor coordination of mice. The mechanisms underlying the abnormal neurological features of kir6.2 deficiency were analyzed by RNA sequencing (RNA-seq). Pm20d1, a gene encoding PM20D1 secretase that promotes the generation of endogenous mitochondria uncouplers in vivo, was dramatically upregulated in the midbrain of kir6.2^−/− mice. Further investigations verified that PM20D1-induced increase of N-acyl amino acids (N-AAAs) from circulating fatty acids and amino acids promoted mitochondrial impairments and cut down the ATP generation, which mediated the morphological defects of the mesencephalic neurons and thus led to the behavioral impairments of kir6.2 knockout mice. This study is the first evidence to demonstrate the roles of kir6.2 in the morphological maintenance of neurite and motor coordination control of mice, which extends our understanding of kir6.2/KATP channels in regulating the neurophysiological function.

Kir6.2 是 ATP 敏感钾 (KATP) 通道的成孔亚基，可调节代谢活跃组织的功能，是多种疾病的理想治疗靶点。以前的研究已经在外周 kir6.2 上进行过，但很少揭示其在中枢神经系统 (CNS) 中的精确生理作用。在目前的研究中，我们评估了 kir6.2 敲除 (kir6.2 ^-/- ) 小鼠的神经表型和神经行为学。我们证明了 kir6.2 对维持中脑神经元形态和控制小鼠运动协调的有益作用。通过 RNA 测序 (RNA-seq) 分析了 kir6.2 缺陷异常神经学特征的机制。下午20d1，一种编码 PM20D1 分泌酶的基因，可促进体内内源性线粒体解偶联剂的产生，在kir6.2 ^-/-小鼠的中脑中显着上调。进一步的研究证实，PM20D1 诱导的循环脂肪酸和氨基酸中 N-酰基氨基酸 (N-AAAs) 的增加促进了线粒体损伤并减少了 ATP 的产生，从而介导了中脑神经元的形态缺陷，从而导致kir6.2 基因敲除小鼠的行为障碍。本研究首次证明了 kir6.2 在小鼠神经突形态维持和运动协调控制中的作用，扩展了我们对 kir6.2/KATP 通道调节神经生理功能的理解。