The Inositol Phosphate-Calcium Signaling System in Nonexcitable Cells

IN 1983, Michael Berridge proposed (1), and subsequently with collaborators demonstrated (2), that d-myo-inositol 1,4,5-trisphosphate (1,4,5)IP3, generated in the course of receptor-activated inositol lipid turnover, was a second messenger signaling the release of stored calcium from intracellular sites to the cytoplasm of activated cells. The significance of this discovery was enormous. The explosion of interest and research in this area in the last decade has demonstrated that the inositol phosphate-calcium signaling system plays a critical role in the mechanisms by which hormones regulate diverse processes such as muscle contraction, cell secretion, metabolism, and cell growth and differentiation. Despite the consensus regarding the central role of (1,4,5)IP3 in intracellular Ca2+ mobilization, the extremely complex nature of Ca2+ signaling and inositol phosphate metabolism has spawned controversies. What is the meaning of the enigmatically complex pathways of inositol phosphate metabolism? Clearly (1,4,5)IP3 is the signal for intracellular Ca2+ release, but how is calcium entry across the plasma membrane regulated? What are the mechanism(s) and physiological significance of calcium oscillations? This review will attempt first to summarize the less controversial aspects of the inositol phosphate-calcium signaling system and then to address some of the more difficult issues. We will not pretend to offer definitive solutions to these quandaries, but we will attempt to identify the major issues of controversy. In some cases, we will speculate on potential directions for their resolution. For the most part, as the title of this review implies, the examples and mechanisms discussed will be drawn from published studies on nonexcitable cells, because these cells appear to express the most fundamental and ubiquitous mechanisms of Ca2+ regulation through the inositol phosphate system. In terms of calcium signaling, we are using the term nonexcitable to indicate absence of voltagegated calcium channels. The reader is also directed to a number of recent publications that address, from a somewhat different perspective, some of the specific topics covered in this review (3–15).