The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

Abstract The inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) type 2 (IP 3 R2) is an intracellular Ca 2 + -release channel located on the endoplasmic reticulum (ER). IP 3 R2 is characterized by a high sensitivity to both IP 3 and ATP and is biphasically regulated by Ca 2 + . Furthermore, IP 3 R2 is modulated by various protein kinases. In addition to its regulation by protein kinase A, IP 3 R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP. Finally, in the ER, IP 3 R2 is less mobile than the other IP 3 R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP 3 R2 a Ca 2 + channel with exquisite properties for setting up intracellular Ca 2 + signals with unique characteristics. IP 3 R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP 3 R2 appears more complex, because, together with IP 3 R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Most importantly, its high sensitivity to IP 3 makes IP 3 R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP 3 R/Bcl-2 interaction therefore leads in those cells to increased Ca 2 + release and apoptosis. Intriguingly, IP 3 R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP 3 R2 and we anticipate that further progress will soon be made in understanding the function of IP 3 R2 in various tissues and organs.