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

• Published in: Journal of neurochemistry Vol. 102; no. 5; pp. 1426 - 1446
• Main Author: Mikoshiba, Katsuhiko
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2007; Blackwell
• Subjects: Animals; Biological and medical sciences; Calcium Channels - physiology; Cell receptors; Cell structures and functions; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; channel; endoplasmic reticulum; Fundamental and applied biological sciences. Psychology; Inositol 1,4,5-Trisphosphate Receptors - physiology; IP3; IP3 receptor; IRBIT; Models, Biological; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Signal Transduction - physiology; Vertebrates: nervous system and sense organs; Inositol 1,4,5-trisphosphate receptor; Calcium; Extracellular calcium-sensing receptor; Rodentia; channel; IP3; IP3 receptor; IRBIT; Strain; Signal transduction; Vertebrata; Mammalia; Mouse; Phosphoproteins; Second messenger; N terminal-Sequence; Cytoskeleton; Microtubule; Exocrine secretion; Diffusion; Endoplasmic reticulum; Release; Inositol 1,4,5-trisphosphate
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04825.x

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.