Resurgent current in context: Insights from the structure and function of Na and K channels

Discovered just over 25 years ago in cerebellar Purkinje neurons, resurgent Na current was originally described operationally as a component of voltage-gated Na current that flows upon repolarization from relatively depolarized potentials and speeds recovery from inactivation, increasing excitability. Its presence in many excitable cells and absence from others has raised questions regarding its biophysical and molecular mechanisms. Early studies proposed that Na channels capable of generating resurgent current are subject to a rapid open-channel block by an endogenous blocking protein, which binds upon depolarization and unblocks upon repolarization. Since the time that this mechanism was suggested, many physiological and structural studies of both Na and K channels have revealed aspects of gating and conformational states that provide insights into resurgent current. These include descriptions of domain movements for activation and inactivation, solution of cryo-EM structures with pore-blocking compounds, and identification of native blocking domains, proteins, and modulatory subunits. Such results not only allow the open-channel block hypothesis to be refined but also link it more clearly to research that preceded it. This review considers possible mechanisms for resurgent Na current in the context of earlier and later studies of ion channels and suggests a framework for future research.