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Abstract
In both nonexcitable and excitable cells, the inositol 1,4,5-trisphosphate receptor (IP3R) is the primary cytosolic target responsible for the initiation of intracellular calcium (Ca2+) signaling. To fulfill this function, the IP3R depends on interaction with accessory subunits and regulatory proteins. These include proteins that reside in the lumen of the endoplasmic reticulum (ER), such as chromogranin A and B and ERp44, and cytosolic proteins, such as neuronal Ca2+ sensor 1, huntingtin, cytochrome c, IP3R-binding protein released with inositol 1,4,5-trisphosphate, Homer, and 4.1N. Specific interactions between these modulatory proteins and the IP3R have been described, making it clear that the controlled modulation of the IP3R by its binding partners is necessary for physiological cell regulation. The functional coupling of these modulators with the IP3R can control apoptosis, intracellular pH, the initiation and regulation of neuronal Ca2+ signaling, exocytosis, and gene expression. The pathophysiological relevance of IP3R modulation is apparent when the functional interaction of these proteins is enhanced or abolished by mutation or overexpression. The subsequent deregulation of the IP3R leads to pathological changes in Ca2+ signaling, signal initiation, the amplitude and frequency of Ca2+ signals, and the duration of the Ca2+ elevation. Consequences of this deregulation include abnormal growth and apoptosis. Complex regulation of Ca2+ signaling is required for the cell to live and function, and this difficult task can only be managed when the IP3R teams up and acts properly with its numerous binding partners.
