The tetrodotoxin-sensitive sodium ion (Na ϩ) channel is opened by cellular depolarization and favors the passage of Na ϩ over other ions. Activation of the ␤-adrenergic receptor or protein kinase A in rat heart cells transformed this Na ϩ channel into one that is promiscuous with respect to ion selectivity, permitting calcium ions (Ca 2ϩ) to permeate as readily as Na ϩ. Similarly, nanomolar concentrations of cardiotonic steroids such as ouabain and digoxin switched the ion selectivity of the Na ϩ channel to this state of promiscuous permeability called slip-mode conductance. Slip-mode conductance of the Na ϩ channel can contribute significantly to local and global cardiac Ca 2ϩ signaling and may be a general signaling mechanism in excitable cells.