Structural electrobiology: architecture of the bioelectric code

Bioelectrical signalling is fundamental for regulating biological processes in all forms of life. Ion channels and transporters generate and propagate electrical currents by selectively allowing ions to flow across membranes in response to voltage changes. Although recent breakthroughs in structural determination methods, such as cryogenic electron microscopy, have provided novel insights into the structure-function relationships of ion channels and scaffolding proteins, their precise roles in bioelectrical signal generation and propagation within and across different cells and tissues remain unresolved. This article examines the biochemical and ultrastructural features of the three most studied modes of bioelectrical conduction in human tissues-electrotonic, saltatory and ephaptic conduction-and how biophysical constraints set by membranes and proteins give rise to bioelectricity. Notably, ion channel clustering and scaffolding proteins that define intermembrane distances are common key features among all forms of bioelectrical signalling. Techniques like cryogenic electron tomography offer promising avenues for exploring ion channels and their regulatory protein interactions in situ. The central question is: 'How does the spatial organization of ions, molecules and tissues give rise to bioelectricity?' These insights may inform novel therapeutic approaches for various diseases, while also potentially offering new perspectives on life, evolution and consciousness.