A Rationally Designed, General Strategy for Membrane Orientation of Photoinduced Electron Transfer-Based Voltage-Sensitive Dyes

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2016 Dec 23

PMID 28004909

Citations 30

Authors

Rishikesh U Kulkarni

Hang Yin

Narges Pourmandi

Feroz James

Maroof M Adil

David V Schaffer

Yi Wang

Evan W Miller

Affiliations

Soon will be listed here.

Abstract

Voltage imaging with fluorescent dyes offers promise for interrogating the complex roles of membrane potential in coordinating the activity of neurons in the brain. Yet, low sensitivity often limits the broad applicability of optical voltage indicators. In this paper, we use molecular dynamics (MD) simulations to guide the design of new, ultrasensitive fluorescent voltage indicators that use photoinduced electron transfer (PeT) as a voltage-sensing switch. MD simulations predict an approximately 16% increase in voltage sensitivity resulting purely from improved alignment of dye with the membrane. We confirm this theoretical finding by synthesizing 9 new voltage-sensitive (VoltageFluor, or VF) dyes and establishing that all of them display the expected improvement of approximately 19%. This synergistic outworking of theory and experiment enabled computational and theoretical estimation of VF dye orientation in lipid bilayers and has yielded the most sensitive PeT-based VF dye to date. We use this new voltage indicator to monitor voltage spikes in neurons from rat hippocampus and human pluripotent-stem-cell-derived dopaminergic neurons.

Citing Articles

Toward measurements of absolute membrane potential in Bacillus subtilis using fluorescence lifetime.

Roy D, Michalet X, Miller E, Bharadwaj K, Weiss S Biophys Rep (N Y). 2025; 5(1):100196.

PMID: 39798601 PMC: 11835658. DOI: 10.1016/j.bpr.2025.100196.

An open and shut case? Chemistry to control xanthene dyes.

Turnbull J, Miller E Trends Chem. 2024; 6(4):164-172.

PMID: 39036609 PMC: 11257214. DOI: 10.1016/j.trechm.2024.01.006.

Towards measurements of absolute membrane potential in Bacillus subtilis using fluorescence lifetime.

Roy D, Michalet X, Miller E, Bharadwaj K, Weiss S bioRxiv. 2024; .

PMID: 38915670 PMC: 11195253. DOI: 10.1101/2024.06.13.598880.

Extended voltage imaging in cardiomyocytes with a triplet state quencher-stabilized silicon rhodamine.

Martinez K, Gerstner N, Yang S, Miller E Bioorg Med Chem Lett. 2024; 109:129842.

PMID: 38844174 PMC: 11648968. DOI: 10.1016/j.bmcl.2024.129842.

Orientation and Membrane Partition Free Energy of PeT-Based Voltage-Sensitive Dyes from Molecular Simulations.

Lam C, Fung L, Wang Y J Phys Chem B. 2024; 128(11):2734-2744.

PMID: 38459942 PMC: 10961725. DOI: 10.1021/acs.jpcb.3c08090.

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