IRBIT regulates CaMKIIα activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation.
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 (CaMKIIα) as an IRBIT-interacting molecule in the central nervous system. IRBIT binds to and suppresses CaMKIIα kinase activity by inhibiting the binding of calmodulin to CaMKIIα. 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 CaMKIIα, which affects TH activity, was significantly increased in the ventral tegmental area of IRBIT-deficient mice. We concluded that IRBIT suppresses CaMKIIα activity and contributes to catecholamine homeostasis through TH phosphorylation.
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan;
Katsuhiro
K
Kawaai
Department of Pharmacotherapeutics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan;
Akihiro
A
Mizutani
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan;
Hirotaka
H
Shoji
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan;
Naoko
N
Ogawa
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan;
Etsuko
E
Ebisui
Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo 160-8582, Japan; and.
Yukiko
Y
Kuroda
Technology and Development Team for Mouse Phenotype Analysis, BioResource Center, RIKEN, Tsukuba, Ibaraki 305-0074, Japan.
Shigeharu
S
Wakana
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan;
Tsuyoshi
http://orcid.org/0000-0003-0137-8200
T
Miyakawa
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan;
Chihiro
C
Hisatsune
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan; mikosiba@brain.riken.jp.
Katsuhiko
K
Mikoshiba
D043383:Adenosylhomocysteinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002395:Catecholamines / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D002395:Catecholamines; D014446:Tyrosine 3-Monooxygenase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; D043383:Adenosylhomocysteinase; C510392:IRBIT protein, mouse
CaMKIIα; IRBIT; catecholamine; hyperactivity