Sense in Pb²⁺ sensing

It is generally acknowledged that Pb(2+), which is sequestered by live cells from their direct environment, affects a large number of cellular processes at picomolar to micromolar concentrations. However, resolving the specific molecular targets and mechanisms responsible for the neurotoxic effects of this xenobiotic metal is hampered by the lack of suitable tools to investigate the intracellular dynamics of Pb(2+) at low concentrations. Fluorescent Ca(2+) indicators have been used as Pb(2+) sensors and have proven useful to detect cellular Pb(2+) entry and to estimate the overall intracellular free Pb(2+) concentration associated with adverse cellular effects. Despite the high affinity of these Ca(2+) indicators for Pb(2+), their utility for more advanced studies is limited. This is merely due to their moderate metal selectivity and uncertainties about the subcellular (co)localization of the indicators and the targets. Novel Pb(2+) sensors, specifically developed for this purpose, still lack affinity to sense toxicologically relevant intracellular concentrations of Pb(2+). Nonetheless, the development of genetically encoded protein sensors for Ca(2+), Zn(2+), and, recently, also for Pb(2+) opens a new and promising perspective to resolve spatiotemporal changes in intracellular Pb(2+) in relation to cellular signaling and intracell ular divalent metal homeostasis. Such a development is required for enabling more systematic studies of the intracellular dynamics of Pb(2+), which are essential for progress in mechanistic knowledge and will ultimately reveal the critical toxic targets of Pb(2+) at the subcellular and molecular level.