IP3 receptor/Ca2+ channel: from discovery to new signaling concepts

Abstract

Inositol 1,4,5‐trisphosphate (IP 3) is a second messenger that induces the release of Ca 2+ from the endoplasmic reticulum (ER). The IP 3 receptor (IP 3 R) was discovered as a developmentally regulated glyco‐phosphoprotein, P400, that was missing in strains of mutant mice. IP 3 R can allosterically and dynamically change its form in a reversible manner. The crystal structures of the IP 3‐binding core and N‐terminal suppressor sequence of IP 3 R have been identified. An IP 3 indicator (known as IP 3 R‐based IP 3 sensor) was developed from the IP 3‐binding core. The IP 3‐binding core’s affinity to IP 3 is very similar among the three isoforms of IP 3 R; instead, the N‐terminal IP 3 binding suppressor region is responsible for isoform‐specific IP 3‐binding affinity tuning. Various pathways for the trafficking of IP 3 R have been identified; for example, the ER forms a meshwork upon which IP 3 R moves by lateral diffusion, and vesicular ER subcompartments containing IP 3 R move rapidly along microtubles using a kinesin motor. Furthermore, IP 3 R mRNA within mRNA granules also moves along microtubules. IP 3 Rs are involved in exocrine secretion. ERp44 works as a redox sensor in the ER and regulates IP 3 R1 activity. IP 3 has been found to release Ca 2+, but it also releases IRBIT (IP 3 R‐binding protein released with IP 3). IRBIT is a pseudo‐ligand for IP 3 that regulates the frequency and amplitude of Ca 2+ oscillations through IP 3 R. 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 IP 3 Rs form a macro signal complex and function as a center for signaling cascades. The structure of IP 3 R1, as revealed by cryoelectron microscopy, fits closely with these molecules.