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Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6

Correspondence to Shetuan Zhang: szhang{at}sbrc.ca

The inactivation gating of hERG channels is important for the channel function and drug–channel interaction. Whereas hERG channels are highly selective for K⁺, we have found that inactivated hERG channels allow Na⁺ to permeate in the absence of K⁺. This provides a new way to directly monitor and investigate hERG inactivation. By using whole cell patch clamp method with an internal solution containing 135 mM Na⁺ and an external solution containing 135 mM NMG⁺, we recorded a robust Na⁺ current through hERG channels expressed in HEK 293 cells. Kinetic analyses of the hERG Na⁺ and K⁺ currents indicate that the channel experiences at least two states during the inactivation process, an initial fast, less stable state followed by a slow, more stable state. The Na⁺ current reflects Na⁺ ions permeating through the fast inactivated state but not through the slow inactivated state or open state. Thus the hERG Na⁺ current displayed a slow inactivation as the channels travel from the less stable, fast inactivated state into the more stable, slow inactivated state. Removal of fast inactivation by the S631A mutation abolished the Na⁺ current. Moreover, acceleration of fast inactivation by mutations T623A, F627Y, and S641A did not affect the hERG Na⁺ current, but greatly diminished the hERG K⁺ current. We also found that external Na⁺ potently blocked the hERG outward Na⁺ current with an IC₅₀ of 3.5 mM. Mutations in the channel pore and S6 regions, such as S624A, F627Y, and S641A, abolished the inhibitory effects of external Na⁺ on the hERG Na⁺ current. Na⁺ permeation and blockade of hERG channels provide novel ways to extend our understanding of the hERG gating mechanisms.

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