Advances in imaging of understudied ions in signaling: A focus on magnesium

The study of metal ions in the context of cell signaling has historically focused mainly on Ca²⁺, the second messenger par excellence. But recent studies support an emerging paradigm in which other metals, including magnesium and d-block metals, play a role in signal transduction as well. Armed with the right indicators, fluorescence microscopy offers a unique combination of spatial and temporal resolution perfectly suited to reveal metal transients in real time, while also helping identify possible sources of ion mobilization and molecular targets. With a focus on Mg²⁺, we highlight recent advancements in the development of molecular indicators and imaging strategies for the study of metal ions in signaling. We discuss remaining conceptual and technical challenges in the field, and we illustrate through the case of Mg²⁺ how the study of nontraditional ions in signaling is inspiring technological developments applicable more broadly to the study of metals in biology.