Distinct Exocytosis Behavior at Synaptic Membrane Protein–Protein Coupled Cell–Electrode Interfaces Revealed by Single‐Cell Amperometry

Abstract Neural interfacing technologies, combined with biospecific targeting and neuroelectrochemical analysis, provide a powerful platform for advancing the understanding of neural communication at the single‐cell level. A key factor in this integration is the role of protein‐mediated cell adhesion at the cell–electrode interface, which can influence cellular processes such as exocytosis. However, the specific impact of this interaction remains largely unexplored. In this study, a biospecific electrode platform functionalized with genetically engineered neuroligin‐2 (eNLG2) is developed and its effect on exocytosis in PC12 cells is investigated. The findings reveal that eNLG2‐modified electrodes significantly slowed exocytosis kinetics and increased the amount of neurotransmitters released per event compared to non‐protein‐modified and laminin‐modified electrodes. These results suggest that synaptic membrane proteins, such as neuroligin and neurexin, modulate vesicle fusion dynamics likely by influencing membrane properties and intracellular signaling. This study highlights the potential of combining biospecific neural interfacing technologies with neuroelectrochemical approaches to gain comprehensive insights into exocytosis and neural communication.