Deciphering voltage-gated Na+ and Ca2+ channels by studying prokaryotic ancestors

•Prokaryotic ancestors provide insights into NaVs and CaVs.•NaVs permeate sodium ions in a partially hydrated form.•Slow inactivation of Na+ channels is likely to involve partial collapse of the pore.•New data support the sliding helix model for voltage-dependent gating.•Structural basis of Ca2+ selectivity and conductance by Ca2+-selective mutants. Voltage-gated sodium channels (NaVs) and calcium channels (CaVs) are involved in electrical signaling, contraction, secretion, synaptic transmission, and other physiological processes activated in response to depolarization. Despite their physiological importance, the structures of these closely related proteins have remained elusive because of their size and complexity. Bacterial NaVs have structures analogous to a single domain of eukaryotic NaVs and CaVs and are their likely evolutionary ancestor. Here we review recent work that has led to new understanding of NaVs and CaVs through high-resolution structural studies of their prokaryotic ancestors. New insights into their voltage-dependent activation and inactivation, ion conductance, and ion selectivity provide realistic structural models for the function of these complex membrane proteins at the atomic level.