Ca²⁺ flux through promiscuous cardiac Na⁺ channels: Slip-mode conductance

The tetrodotoxin-sensitive sodium ion (Na⁺) channel is opened by cellular depolarization and favors the passage of Na⁺ over other ions. Activation of the β-adrenergic receptor or protein kinase A in rat heart cells transformed this Na⁺ channel into one that is promiscuous with respect to ion selectivity, permitting calcium ions (Ca²⁺) to permeate as readily as Na⁺. Similarly, nanomolar concentrations of cardiotonic steroids such as ouabain and digoxin switched the ion selectivity of the NA⁺ channel to this state of promiscuous permeability called slip-mode conductance. Slip-mode conductance o the Na⁺ channel can contribute significantly to local and global cardiac Ca²⁺ signaling and may be a general signaling mechanism in excitable cells.