ABSTRACT Inositol 1,4,5-trisphosphate receptors (IP3Rs) are very large tetrameric Ca2+ channels located in the endoplasmic reticulum (ER). IP3Rs are transmembrane proteins with the channel domain in the C-terminal part of the protein and a very large cytoplasmic structure with the IP3-binding domain in the extreme N-terminus. The general structure and the cellular location of these intracellular Ca2+ channels make them ideally suited as collectors and integrators of a broad array of cellular signals, which are then converted into a Ca2+ signal. The biochemical and the functional evidence supports the notion that proteins involved in signaling cascades may be physically coupled, and protein-protein interactions are involved in the regulation and proper functioning of IP3-induced signaling. In a first part we will discuss the proteins that mediate the feedback regulation of the IP3R by cytoplasmic Ca2+. A second part will deal with the regulation of the phosphorylation status by calcineurin, which is anchored to the IP3R by the immunophilin FKBP12. Finally we will summarize the evidence for interaction of the IP3R with plasma membrane proteins e.g. Ca2+ -entry channels, the metabotropic glutamate receptor and G proteins. From the available evidence it is very tempting to speculate about physical connections that may tightly regulate and restrict IP3R-mediated responses in order to make them specifically coupled to particular cellular needs. It should be pointed out, however, that notwithstanding the elegance of the proposed concepts, there remains a lack of firm molecular and functional evidence. Many of the data await further confirmation and exploration in order to understand fully the molecular machinery responsible for IP3-mediated Ca2+ signaling.
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