The IP_3 receptor/Ca~(2+) channel and its cellular function

摘要

The IP3R [IP_3 (inositol 1,4,5-trisphosphate) receptor] is responsible for Ca~(2+) release from the ER (endoplasmic reticulum). We have been working extensively on the P_(400)protein, which is deficient in Purkinje-neuron-degenerating mutant mice. We have discovered that P_(400) is an IP_3R and we have determined the primary sequence. Purified IP_3R, when incorporated into a lipid bilayer, works as a Ca~(2+) release channel and overexpression of IP_3R shows enhanced IP_3 binding and channel activity. Addition of an antibody blocks Ca~(2+) oscillations indicating that IP_3R1 works as a Ca~(2+) oscillator. Studies on the role of IP_3R during development show that IP_3R is involved in fertilization and is essential for determination of dorso-ventral axis formation. We found that IP_3R is involved in neuronal plasticity. A double homozygous mutant of IP_3R2 (IP3R type 2) and IP_3R3 (IP_3R type 3) shows a deficit of saliva secretion and gastric juice secretion suggesting that IP_3Rs are essential for exocrine secretion. IP_3R has various unique properties: cryo-EM (electron microscopy) studies show that IP_3R contains multiple cavities; IP_3R allosterically and dynamically changes its form reversibly (square form-windmill form); IP_3R 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 IP_3 binding core consists of an N-terminal beta-trefoil domain and a C-terminal a-helical domain. We have discovered ERp44 as a redox sensor in the ER which binds to the luminal part of IP_3R1 and regulates its activity. We have also found the role of IP_3 is not only to release Ca~(2+) but also to release IRBIT which binds to the IP_3 binding core of IP3R.