Three inositol 1,4,5-trisphosphate receptor (IP3R) subtypes are differentially expressed among tissues and function as the Ca2+ release channel on specialized endoplasmic reticulum (ER) membranes. The proper subcellular localization of IP3R is crucial for its proper function, but this molecular mechanism is unclear. KRAS-induced actin-interacting protein (KRAP) was originally identified as a cancer-related molecule, and is involved in the regulation of whole-body energy homeostasis and pancreatic exocrine system. We herein identified IP3R as an associated molecule with KRAP in vivo, and the association was validated by the co-immunoprecipitation and confocal immunostaining studies in mouse tissues including liver and pancreas. The association of KRAP with IP3R was also observed in the human epithelial cell lines including HCT116, HeLa and HEK293 cells. Intriguingly, KRAP interacts with distinct subtypes of IP3R in a tissue-dependent manner, i.e. IP(3)R1 and IP(3)R2 in the liver and IP(3)R2 and IP(3)R3 in the pancreas. The NH2-terminal amino acid residues 1-610 of IP3R are critical for the association with KRAP and KRAP-IP3R complex resides in a specialized ER but not a typical reticular ER. Furthermore, the localization of particular IP3R subtypes in tissues from KRAP-deficient mice is obviously disturbed, i.e. IP(3)R1 and IP(3)R2 in the liver and IP(3)R2 and IP(3)R3 in the pancreas. These findings demonstrate that KRAP physically associates with IP3R and regulates the proper localization of IP3R in the epithelial cells in vivo and cultured cells, and might shed light on the Ca2+ signaling underlying physiological cellular programs, cancer development and metabolism-related diseases. (C) 2011 Elsevier Inc. All rights reserved.