期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：5515-5520
DOI：10.1073/pnas.1503310112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAppropriate homeostatic regulation of catecholamines (dopamine, norepinephrine) is important for the maintenance of normal brain function and mental state. The dysregulation of dopamine systems has been correlated with a hyperactive phenotype and social abnormalities, which are frequently observed in patients with psychiatric disorders. In this report, we found that IRBIT regulates catecholamine homeostasis by binding to calcium calmodulin-dependent kinase II alpha and subsequently controlling tyrosine hydroxylase phosphorylation. In addition, mice lacking IRBIT present with increased locomotor activity and social abnormalities. Our finding provides new insight into the homeostatic regulation of catecholamines. Inositol 1,4,5-trisphosphate receptor (IP3R) binding protein released with IP3 (IRBIT) contributes to various physiological events (electrolyte transport and fluid secretion, mRNA polyadenylation, and the maintenance of genomic integrity) through its interaction with multiple targets. However, little is known about the physiological role of IRBIT in the brain. Here we identified calcium calmodulin-dependent kinase II alpha (CaMKII) as an IRBIT-interacting molecule in the central nervous system. IRBIT binds to and suppresses CaMKII kinase activity by inhibiting the binding of calmodulin to CaMKII. In addition, we show that mice lacking IRBIT present with elevated catecholamine levels, increased locomotor activity, and social abnormalities. The level of tyrosine hydroxylase (TH) phosphorylation by CaMKII, which affects TH activity, was significantly increased in the ventral tegmental area of IRBIT-deficient mice. We concluded that IRBIT suppresses CaMKII activity and contributes to catecholamine homeostasis through TH phosphorylation.
