IP3 receptor/Ca2+ channel: from discovery to new signaling concepts
Article first published online: 17 JUL 2007
Journal of Neurochemistry
Volume 102, Issue 5, pages 1426–1446, September 2007
How to Cite
Mikoshiba, K. (2007), IP3 receptor/Ca2+ channel: from discovery to new signaling concepts. Journal of Neurochemistry, 102: 1426–1446. doi: 10.1111/j.1471-4159.2007.04825.x
- Issue published online: 17 JUL 2007
- Article first published online: 17 JUL 2007
- Received May 7, 2007; revised manuscript received June 22, 2007; accepted July 2, 2007.
- endoplasmic reticulum;
- IP3 receptor;
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.