New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreatic β-Cell

Studies of inositol polyphosphates in the pancreatic beta-cell have led to an exciting synergism between new discoveries regarding their cellular roles and new insights into beta-cell function. Because the loss or malfunction of the beta-cell is central to diabetes, these studies open the possibility of new pharmacological interventions in a disease that has reached epidemic proportions worldwide. Using the beta-cell as our prime but not exclusive example, we examine the inositol polyphosphates in three main groups: 1) inositol 1,4,5-trisphosphate and its influence on Ca2+ signaling, specifically in a cell in which cytoplasmic-free Ca2+ concentration is principally increased by plasma membrane standing voltage-gated Ca2+ channels; 2) higher inositol polyphosphates including a novel second messenger inositol 3,4,5,6-tetrakisphosphate and a regulatory role for inositol hexakisphosphate in beta-cell Ca2+ homeostasis and exo- and endocytosis; and 3) inositol pyrophosphates and their role in beta-cell exocytosis, together with the exciting possibility of being novel targets for therapy in diabetes. We conclude with some of the new perspectives that are likely to become apparent in the next few years.