# Uncovering the Lipid Interface in Neurotransmission: Single Molecule Measurements of Neurotransmitters Interacting with Membranes Reveal Species Dependent Membrane Binding

## TL;DR

This study shows that neurotransmitters interact differently with cell membranes, with some binding stably and others only briefly, suggesting the membrane plays an active role in signaling.

## Contribution

The study introduces a novel single-molecule method using WGM sensors to directly measure neurotransmitter-membrane interactions.

## Key findings

- Aromatic neurotransmitters like histamine and dopamine show stable membrane binding, while amino acid-like ones do not.
- Kinetic analyses reveal species-dependent association and dissociation rates of neurotransmitters with lipid bilayers.
- Langmuir trough experiments confirm histamine's membrane partitioning but not glycine's.

## Abstract

Neurotransmitters (NTs) have traditionally been understood to act via aqueous‐phase receptor binding, but growing evidence suggests the lipid bilayer plays an active role in modulating their signalling. Here, single‐molecule measurements are presented using whispering gallery mode (WGM) optical sensors to directly observe NT interactions with supported lipid bilayers. Aromatic NTs, such as histamine, dopamine, epinephrine, and L‐norepinephrine, exhibit stable, step‐like resonance shifts, indicating sustained membrane association, while amino acid‐like NTs generate only transient interactions. Kinetic analyses of spike and step events reveal species‐dependent association and dissociation rates. Complementary Langmuir trough experiments confirm membrane partitioning by the NT histamine, but not by glycine. These findings support a model of selective membrane partitioning in neurotransmission and highlight the bilayer as an active participant in NT signalling. This work advances the understanding of NT–membrane interactions and provides a platform for probing non‐canonical modes of synaptic communication.

Using single‐molecule whispering gallery mode sensors, neurotransmitter‐specific membrane binding signatures are measured that reveal intrinsically distinct interaction kinetics and orientations on a lipid membrane.