8.A.151. The IP₃R binding protein released with inositol 1,4,5-trisphosphate (IRBIT) Family
The IP₃ receptor (IP₃R) is a Ca2+ channel that releases Ca2+ from the endoplasmic reticulum (ER) and plays a variety of roles in cell functions. Its activity is regulated by direct interaction with the IRBIT protein (TC# 8.A.151.1.1). IP₃ binding to the IP₃-binding core leads to a conformational change, resulting in direct interactions of tyrosine-168 (in IP₃R1)/tryptophane-168 (in IP₃R2 and 3) in the N-terminal suppressor region with the loop region of transmembrane 4-5. The suppressor region and C-terminal -portion which associate with nearly 20 signaling molecules are located at the areas near the channel pore. The area including suppressor region and C-terminal portion are regarded as hot spots for the regulating opening and closing of the channel pore. A pseudo-ligand of the IP₃R, known as IRBIT (IP₃R binding protein released with inositol 1,4,5-trisphosphate), that interacts with the IP₃-binding core domain of the IP₃R was discovered. IRBIT not only regulates Ca(2+) release by binding to the IP₃-binding core domain but also regulates the acid-base balance by binding to various ion transporters, such as pancreas-type NBC1 (pNBC1) and CFTR (Mikoshiba 2012). IRBIT activates NBCe1-B by releasing the auto-inhibition module from the transmembrane domain (Su et al. 2020). IRBIT is also called: S-adenosylhomocysteine hydrolase-like protein 1, suggesting that it's primary function of that of a hydrolase.