# Ultrafast Genetically Encoded Voltage Indicators Designed from First Principles

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $442,179

## Abstract

ABSTRACT:
 The ability to optically record neuronal electrical activity with the temporal and fine-feature waveform
resolution on par with whole-cell patch clamp electrophysiology would permit the correlation, of the physiology
of individual cells and cell types, to the neural circuit-level activity that underlies behaviors, cognition, and
affective states observed in the normal and diseased brain. Genetically encoded voltage indicators (GEVIs)
hold great promise for this purpose as cell-type specific probes, if their voltage-sensitivity, brightness, and
temporal resolution can be engineered to provide the reliable detection of high frequency action potentials, the
detection of sub-threshold “minis” critical to synaptic scaling and homeostatic plasticity, and the ability to
resolve waveforms useful for deducing specific channel/receptor contributions to spiking and synaptic
transmission. We propose to invent next-generation GEVIs through rational design from first principles of non-
biologically derived proteins. We will adapt artificial protein “maquettes,” which are de novo-designed and rigid
4-helix bundle proteins that serve as custom scaffolds for arbitrarily positioning biological co-factors within the
scaffold core. Strategic positioning of a biliverdin chromphore within a transmembrane maquette allows for
voltage sensing by the optical Stark effect, in which chromophores exhibit electric field-induced changes in
absorbance that result in ultrafast changes in observed fluorescence. We call these proteins, “MASTERs”
(Maquette Stark Effect Reporters). The ultrafast infrared-fluorescent reporters will recapitulate whole-cell
recordings with no observable delay or waveform difference.

## Key facts

- **NIH application ID:** 10148825
- **Project number:** 5R01NS101106-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Bohdana Discher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,179
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148825

## Citation

> US National Institutes of Health, RePORTER application 10148825, Ultrafast Genetically Encoded Voltage Indicators Designed from First Principles (5R01NS101106-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148825. Licensed CC0.

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