# Engineering synthetic proteins for electron transfer based ultrafast sensing of membrane potentials

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $237,389

## Abstract

Project summary
 Unraveling complex behavior of healthy and diseased brain by analyzing the structure and dynamics of
neural circuitry with single action potential resolution is a long-standing goal for neuroscience. While many
voltage-sensitive indicators have been developed for direct imaging of cellular membrane potentials, realization
of their in vivo potential is still compromised by toxicity, time resolution and signal weakness arising from
nonspecific background labeling, low quantum yields, limited dynamic range and signal dampening from
increased cellular capacitance. Here we take a novel approach using de novo designed proteins to secure a
transmembrane redox chain of endogenous heme and respond to changes in membrane potential at the speed
of electron tunneling. We propose to exploit the adaptability of de novo protein design to gain leveraged
microsecond voltage sensitivity, sufficiently fast to resolve the entire action potential waveforms in neurons.
Optical detection of the proposed transmembrane electron-transfer relay will be achieved via energy transfer
with fused genetically encoded fluorescent proteins. We expect these voltage sensors to be dramatically faster
and more tunable than current genetically encoded voltage indicators (GEVIs) based on voltage-dependent
protein structural rearrangements with fundamental kinetic limit of ~0.5 millisecond. When developed, these
sensors will greatly advance optical imaging of neural activity, thereby accelerating progress toward
understanding how brain activity governs human behavior, cognition, and abnormal pathologies.

## Key facts

- **NIH application ID:** 9947987
- **Project number:** 5R21EB027407-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Bohdana Discher
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,389
- **Award type:** 5
- **Project period:** 2018-09-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947987

## Citation

> US National Institutes of Health, RePORTER application 9947987, Engineering synthetic proteins for electron transfer based ultrafast sensing of membrane potentials (5R21EB027407-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9947987. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*