The IP₃ receptor/Ca²⁺ channel and its cellular function

The IP₃R [IP₃ (inositol 1,4,5-trisphosphate) receptor] is responsible for Ca²⁺ release from the ER (endoplasmic reticulum). We have been working extensively on the P₄₀₀ protein, which is deficient in Purkinje-neuron-degenerating mutant mice. We have discovered that P₄₀₀ is an IP₃R and we have determined the primary sequence. Purified IP₃R, when incorporated into a lipid bilayer, works as a Ca²⁺ release channel and overexpression of IP₃R shows enhanced IP₃ binding and channel activity. Addition of an antibody blocks Ca²⁺ oscillations indicating that IP₃R1 works as a Ca²⁺ oscillator. Studies on the role of IP₃R during development show that IP₃R is involved in fertilization and is essential for determination of dorso-ventral axis formation. We found that IP₃R is involved in neuronal plasticity. A double homozygous mutant of IP₃R2 (IP₃R type 2) and IP₃R3 (IP₃R type 3) shows a deficit of saliva secretion and gastric juice secretion suggesting that IP₃Rs are essential for exocrine secretion. IP₃R has various unique properties: cryo-EM (electron microscopy) studies show that IP₃R contains multiple cavities; IP₃R allosterically and dynamically changes its form reversibly (square form–windmill form); IP₃R is functional even though it is fragmented by proteases into several pieces; the ER forms a meshwork but also forms vesicular ER and moves along microtubules using a kinesin motor; X ray analysis of the crystal structure of the IP₃ binding core consists of an N-terminal β-trefoil domain and a C-terminal α-helical domain. We have discovered ERp44 as a redox sensor in the ER which binds to the luminal part of IP₃R1 and regulates its activity. We have also found the role of IP₃ is not only to release Ca²⁺ but also to release IRBIT which binds to the IP₃ binding core of IP₃R.