The Inositol 1,4,5-Trisphosphate Receptor (IP₃R) and Its Regulators: Sometimes Good and Sometimes Bad Teamwork

Chi-un Choe^1,2 and Barbara E. Ehrlich^1*

¹Departments of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
²Institute for Neural Signal Transduction, Zentrum für Molekulare Neurobiologie Hamburg, University of Hamburg, 20251 Hamburg, Germany.

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.

*Corresponding author. E-mail, barbara.ehrlich{at}yale.edu

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