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

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP(3)R2) is an intracellular Ca2+-release channel located on the endoplasmic reticulum (ER). IP(3)R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca2+. 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 IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP(3)R2 a Ca2+ channel with exquisite properties for setting up intracellular Ca2+ 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 IP3 makes IP(3)R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca2+ 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. (C) 2014 Elsevier B.V. All rights reserved.