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Keywords:

  • channel;
  • endoplasmic reticulum;
  • IP3;
  • IP3 receptor;
  • IRBIT

Abstract

Inositol 1,4,5-trisphosphate (IP3) is a second messenger that induces the release of Ca2+ from the endoplasmic reticulum (ER). The IP3 receptor (IP3R) was discovered as a developmentally regulated glyco-phosphoprotein, P400, that was missing in strains of mutant mice. IP3R can allosterically and dynamically change its form in a reversible manner. The crystal structures of the IP3-binding core and N-terminal suppressor sequence of IP3R have been identified. An IP3 indicator (known as IP3R-based IP3 sensor) was developed from the IP3-binding core. The IP3-binding core’s affinity to IP3 is very similar among the three isoforms of IP3R; instead, the N-terminal IP3 binding suppressor region is responsible for isoform-specific IP3-binding affinity tuning. Various pathways for the trafficking of IP3R have been identified; for example, the ER forms a meshwork upon which IP3R moves by lateral diffusion, and vesicular ER subcompartments containing IP3R move rapidly along microtubles using a kinesin motor. Furthermore, IP3R mRNA within mRNA granules also moves along microtubules. IP3Rs are involved in exocrine secretion. ERp44 works as a redox sensor in the ER and regulates IP3R1 activity. IP3 has been found to release Ca2+, but it also releases IRBIT (IP3R-binding protein released with IP3). IRBIT is a pseudo-ligand for IP3 that regulates the frequency and amplitude of Ca2+ oscillations through IP3R. IRBIT binds to pancreas-type Na, bicarbonate co-transporter 1, which is important for acid-base balance. The presence of many kinds of binding partners, like homer, protein 4.1N, huntingtin-associated protein-1A, protein phosphatases (PPI and PP2A), RACK1, ankyrin, chromogranin, carbonic anhydrase-related protein, IRBIT, Na,K-ATPase, and ERp44, suggest that IP3Rs form a macro signal complex and function as a center for signaling cascades. The structure of IP3R1, as revealed by cryoelectron microscopy, fits closely with these molecules.