The Inositol 1,4,5-Trisphosphate Receptor (IP 3 R) and Its Regulators: Sometimes Good and Sometimes Bad Teamwork

Abstract

In both nonexcitable and excitable cells, the inositol 1,4,5-trisphosphate receptor (IP 3 R) is the primary cytosolic target responsible for the initiation of intracellular calcium (Ca 2+ ) signaling. To fulfill this function, the IP 3 R 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 Ca 2+ sensor 1, huntingtin, cytochrome c, IP 3 R-binding protein released with inositol 1,4,5-trisphosphate, Homer, and 4.1N. Specific interactions between these modulatory proteins and the IP 3 R have been described, making it clear that the controlled modulation of the IP 3 R by its binding partners is necessary for physiological cell regulation. The functional coupling of these modulators with the IP 3 R can control apoptosis, intracellular pH, the initiation and regulation of neuronal Ca 2+ signaling, exocytosis, and gene expression. The pathophysiological relevance of IP 3 R modulation is apparent when the functional interaction of these proteins is enhanced or abolished by mutation or overexpression. The subsequent deregulation of the IP 3 R leads to pathological changes in Ca 2+ signaling, signal initiation, the amplitude and frequency of Ca 2+ signals, and the duration of the Ca 2+ elevation. Consequences of this deregulation include abnormal growth and apoptosis. Complex regulation of Ca 2+ signaling is required for the cell to live and function, and this difficult task can only be managed when the IP 3 R teams up and acts properly with its numerous binding partners.