Morphological Control of Inositol-1,4,5-Trisphosphate–Dependent Signals

Inositol-1,4,5-trisphosphate (InsP₃)-mediated calcium signals represent an important mechanism for transmitting external stimuli to the cell. However, information about intracellular spatial patterns of InsP₃ itself is not generally available. In particular, it has not been determined how the interplay of InsP₃ generation, diffusion, and degradation within complex cellular geometries can control the patterns of InsP₃ signaling. Here, we explore the spatial and temporal characteristics of [InsP₃]_cyt during a bradykinin-induced calcium wave in a neuroblastoma cell. This is achieved by using a unique image-based computer modeling system, Virtual Cell, to integrate experimental data on the rates and spatial distributions of the key molecular components of the process. We conclude that the characteristic calcium dynamics requires rapid, high-amplitude production of [InsP₃]_cyt in the neurite. This requisite InsP₃ spatiotemporal profile is provided, in turn, as an intrinsic consequence of the cell's morphology, demonstrating how geometry can locally and dramatically intensify cytosolic signals that originate at the plasma membrane. In addition, the model predicts, and experiments confirm, that stimulation of just the neurite, but not the soma or growth cone, is sufficient to generate a calcium response throughout the cell.