The plasma membrane actively influences ligand concentrations in its immediate vicinity | Department of Biophysics and Cell Biology

In both experimental and applied medicine, it seems trivial that if we want to stimulate a receptor located in the cell membrane from the extracellular space, then we increase the concentration of the ligand in the extracellular space to a given, typically nanomolar-micromolar value, and we believe that this concentration is more or less homogeneous in the space around the cells. We have demonstrated by fluorescence correlation spectroscopy measurements that this assumption is not fulfilled for the epidermal growth factor (EGF), since the concentration of EGF showed one or two peaks around the cells. The peak located a few micrometers from the membrane (A), which appeared around all EGF receptor-expressing cells, is the consequence of the active membrane turnover. EGF bound to the receptor is almost immediately endocytosed, and some of these vesicles immediately release their contents back into the extracellular space. When this active membrane turnover was inhibited, the ligand concentration peak close to the cell membrane disappeared. When the cells also expressed the ErbB2 receptor, another concentration peak was also created or strengthened, which was 10-20 micrometers away from the membrane (B). The extracellular matrix produced by the cells is responsible for this phenomenon, which, on the one hand, slows down the diffusion and, on the other hand, as a result, locally increases the concentration of EGF. These results have far-reaching consequences, since the above-described active functions of the cell or the cell membrane significantly influence concentrations measured around the cell membrane, so when a ligand is administered, be it an experimentally applied agent or a drug used in clinical practice, the expected and actual concentrations may differ significantly. The authors published their observations in iScience (https://doi.org/10.1016/j.isci.2025.112954).