School of Pharmaceutical Sciences, Guizhou University, Guiyang, China.
Department of Neurology, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, China.
FEBS Lett. 2024 Feb;598(4):400-414. doi: 10.1002/1873-3468.14815. Epub 2024 Feb 1.
The insulin and dopaminergic systems in the brain are associated with schizophrenia and Parkinson's disease with respect to etiology and treatment. The present study investigated the crosstalk between the insulin receptor (IR) and dopamine receptor and found that insulin stimulation selectively inhibits signaling of D R in a PKCβII-dependent manner. Upon insulin stimulation, E3 ligase enzyme Mdm2 moves out of the nucleus to ubiquitinate PKCβII. Subsequently, ubiquitinated PKCβII translocates to the cell membrane and interacts with D R in a phosphorylation-dependent manner at S229/257, resulting in the attenuation of D R signaling and initiating clathrin-mediated endocytosis and downregulation. Considering that both IR and D R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder.
脑内的胰岛素和多巴胺能系统与精神分裂症和帕金森病在病因和治疗上有关联。本研究调查了胰岛素受体 (IR) 和多巴胺受体之间的串扰，发现胰岛素刺激以蛋白激酶 CβII 依赖的方式选择性地抑制 D R 的信号传导。胰岛素刺激后，E3 连接酶 Mdm2 从核内移出，泛素化蛋白激酶 CβII。随后，泛素化的蛋白激酶 CβII 易位到细胞膜，并与 D R 在 S229/257 处发生磷酸化依赖性相互作用，导致 D R 信号转导减弱，并启动网格蛋白介导的内吞作用和下调。鉴于 IR 和 D R 都与一些神经精神疾病密切相关，本研究可为该疾病的病因提供新的分子见解。
