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<p>The ability to non-invasively monitor membrane potential
dynamics in excitable cells like neurons and cardiomyocytes promises to
revolutionize our understanding of the physiology and pathology of the brain
and heart. Here, we report the design, synthesis, and application of a new class
of fluorescent voltage indicator that makes use of a fluorene-based molecular
wire as a voltage sensing domain to provide fast and sensitive measurements of
membrane potential in both mammalian neurons and human-derived cardiomyocytes.
We show that the best of the new probes, fluorene VoltageFluor 2 (fVF 2)
readily reports on action potentials in mammalian neurons, detects
perturbations to cardiac action potential waveform in human induced pluripotent
stem cell (hiPSC)-derived cardiomyocytes, shows a substantial decrease in
phototoxicity compared to existing molecular wire-based indicators, and can
monitor cardiac action potentials for extended periods of time. Together, our
results demonstrate the generalizability of a molecular wire approach to
voltage sensing and highlights the utility of fVF 2 for interrogating membrane
potential dynamics.</p>
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