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Voltage-gated Na channels in many neurons, including several in the cerebellum and brainstem, are specialized to allow rapid firing of action potentials. Repetitive firing is facilitated by resurgent Na current, which flows upon repolarization as Na channels recover through open states from block by an endogenous protein. The best candidate blocking protein to date is Na(V)β4. The sequence of this protein diverges among species, however, while high-frequency firing is maintained, raising the question of whether the proposed blocking action of the Na(V)β4 cytoplasmic tail has been conserved. Here, we find that, despite differences in the Na(V)β4 sequence, Purkinje cells isolated from embryonic chick have resurgent currents with kinetics and amplitudes indistinguishable from those in mouse Purkinje cells. Furthermore, synthetic peptides derived from the divergent Na(V)β4 cytoplasmic tails from five species have the capacity to induce resurgent current in mouse hippocampal neurons, which lack a functional endogenous blocking protein. These data further support a blocking role for Na(V)β4 and also indicate the relative importance of different residues in inducing open-channel block. To investigate the contribution of the few highly conserved residues to open-channel block, we synthesized several mutant peptides in which the identities and relative orientations of a phenylalanine and two lysines were disrupted. These mutant peptides produced currents with vastly different kinetics than did the species-derived peptides, suggesting that these residues are required for an open-channel block that approximates physiological resurgent Na current. Thus, if other blocking proteins exist, they may share these structural elements with the Na(V)β4 cytoplasmic tail.

Cross-Species Conservation of Open-Channel Block by Na Channel β4 Peptides Reveals Structural Features Required for Resurgent Na Current