Unravelling the Turn-On Fluorescence Mechanism of a Fluorescein-Based Probe in GABA(A) Receptors

Author(s)

Nadja K. Singer, Pedro A. Sanchez-Murcia, Margot Ernst, Leticia Gonzalez

Abstract

GABA A (γ-aminobutyric acid type A) receptors are ligand-gated ion channels mediating fast inhibitory transmission in the mammalian brain. Here we report the molecular and electronic mechanism governing the turn-on emission of a fluorescein-based imaging probe able to target the human GABA A receptor. Multiscale calculations evidence a drastic conformational change of the probe from folded in solution to extended upon binding to the receptor. Intramolecular ππ-stacking interactions present in the folded probe are responsible for quenching fluorescence in solution. In contrast, unfolding within the GABA A receptor changes the nature of the bright excited state triggering emission. Remarkably, this turn-on effect only manifests for the dianionic prototropic form of the imaging probe, which is found to be the strongest binder to the GABA A receptor. This study is expected to assist the design of new photoactivatable screening tools for allosteric modulators of the GABA A receptor.

Organisation(s)

Department of Theoretical Chemistry, Research Platform Accelerating Photoreaction Discovery

External organisation(s)

Medizinische Universität Graz, Medizinische Universität Wien, Vienna Doctoral School in Chemistry (DoSChem)

Journal

Angewandte Chemie (International Edition)

Volume

61

No. of pages

8

ISSN

1433-7851

DOI

https://doi.org/10.1002/anie.202205198

Publication date

07-2022

Peer reviewed

Yes

Austrian Fields of Science 2012

104017 Physical chemistry, 104022 Theoretical chemistry

Keywords

ASJC Scopus subject areas

General Chemistry, Catalysis

Portal url

https://ucrisportal.univie.ac.at/en/publications/34ad69e1-7f10-426d-a402-2bccf20cf3d2