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Molecular recording of calcium signaling via calcium-dependent protein proximity labeling

Calcium ions serve as key intracellular signals. Local, transient increases in calcium concentrations can activate calcium sensor proteins that in turn trigger downstream effectors. In neurons, calcium transients play a central role in regulating key neuronal processes including neurotransmitter release and synaptic plasticity. However, it is challenging to capture the molecular events associated with these localized and ephemeral calcium signals. Here we report the development of an engineered biotin ligase that combines the power of genetically encoded calcium indicators with protein proximity labeling. The enzyme, Cal-ID, biotinylates nearby proteins within minutes in response to elevated local calcium levels. The biotinylated proteins can be visualized by microscopy and identified via mass spectrometry. Cal-ID applied to mouse neurons showed increased biotinylation in active neurons, and mass spectrometry revealed active calcium signaling near Plasma Membrane Ca2+ ATPases. Therefore, we present Cal-ID as a biochemical recorder of calcium signaling and neuronal activity.