Mdm2-mediated ubiquitination of PKCβII is responsible for insulin-induced heterologous desensitization of dopamine D3 receptor

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 D₃ 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 D₃ R in a phosphorylation-dependent manner at S229/257, resulting in the attenuation of D₃ R signaling and initiating clathrin-mediated endocytosis and downregulation. Considering that both IR and D₃ R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder.

D3 dopamine receptor; clathrin-mediated endocytosis; desensitization; downregulation; insulin receptor; protein kinase C.