SUMMARY The resurgent component of voltage-gated Na+ (Nav) currents, INaR, has been suggested to provide the depolarizing drive for high frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory Navβ4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (Navβ4) on INaR and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4b−/− animals have deficits in motor coordination and balance and that firing rates in Scn4b−/− Purkinje neurons are markedly attenuated. Acute, in vivo shRNA-mediated “knockdown” of Navβ4 in adult Purkinje neurons also reduced spontaneous and evoked firing rates. Dynamic clamp-mediated addition of INaR partially rescued firing in Scn4b−/− Purkinje neurons. Voltage-clamp experiments revealed that INaR was reduced (by ~50%), but not eliminated, in Scn4b−/− Purkinje neurons, revealing that additional mechanisms contribute to generation of INaR.

and are differentially expressed in nonfailing human LV, contributing to regional heterogeneities in AP waveforms. regulates notch and plateau potentials and modulates the time course and amplitude of . Slowing inactivation results in dramatic AP shortening. Remodeling of in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.

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The transient outward potassium current (Ito) plays a key, albeit incompletely defined, role in cardiomyocyte physiology and pathophysiology.