# Local ligand concentration gradients induced by the plasma membrane

## TL;DR

The study shows that ligand concentrations near the cell membrane are uneven, affecting receptor behavior and signaling.

## Contribution

The paper reveals that membrane turnover and extracellular matrix interactions create concentration gradients of ligands near the plasma membrane.

## Key findings

- EGF concentration peaks near the membrane due to membrane turnover.
- A second EGF peak occurs farther from the membrane in ErbB2-expressing cells due to hindered diffusion.
- These concentration gradients alter receptor-ligand affinity and cooperativity.

## Abstract

The plasma membrane is a dynamic structure surrounded by the extracellular matrix. Although stimulation of transmembrane proteins by soluble ligands takes place in this environment, its influence on receptor activation is usually overlooked. In the current manuscript, we quantitatively measured the concentration of epidermal growth factor (EGF) at the cell membrane and found that ligand distribution is non-homogeneous due to two concentration peaks causing significantly higher EGF concentrations at the membrane than in the bulk solution. Using experiments, calculations, and simulations, we show that the membrane-proximal peak is caused by membrane turnover, while the more distant one, only present in ErbB2-expressing cells, is generated by locally hindered diffusion possibly caused by the extracellular matrix. Both theory and experiments reveal that these phenomena increase the apparent affinity and decrease the apparent cooperativity of the receptor-ligand complex. Interpretation of the effects of soluble ligands interacting with receptors must involve this non-homogenous concentration profile.

•Concentration of externally applied ligands near the cell membrane is heterogeneous•The membrane proximal peak is related to membrane turnover•The membrane distal peak is related to increased microviscosity•This phenomenon may alter the apparent affinity and cooperativity of receptors

Concentration of externally applied ligands near the cell membrane is heterogeneous

The membrane proximal peak is related to membrane turnover

The membrane distal peak is related to increased microviscosity

This phenomenon may alter the apparent affinity and cooperativity of receptors

Theoretical physics; Biological sciences; Membranes; Biophysics; Computer simulation