PF-06526290 can both enhance and inhibit conduction through voltage-gated sodium channels.

BACKGROUND AND PURPOSE

Pharmacological agents that either inhibit or enhance flux of ions through voltage-gated sodium (Na ) channels may provide opportunities for treatment of human health disorders. During studies to characterize agents that modulate Na 1.3 function, we identified a compound that appears to exhibit both enhancement and inhibition of sodium ion conduction that appeared to be dependent on the gating state that the channel was in. The objective of the current study was to determine if these different modulatory effects are mediated by the same or distinct interactions with the channel.

EXPERIMENTAL APPROACH

Electrophysiology and site-directed mutation were used to investigate the effects of PF-06526290 on Na channel function.

KEY RESULTS

PF-06526290 greatly slows inactivation of Na channels in a subtype-independent manner. However, upon prolonged depolarization to induce inactivation, PF-06526290 becomes a Na subtype-selective inhibitor. Mutation of the domain 4 voltage sensor modulates inhibition of Na 1.3 or Na 1.7 channels by PF-06526290 but has no effect on PF-06526290 mediated slowing of inactivation.

CONCLUSIONS AND IMPLICATIONS

These findings suggest that distinct interactions may underlie the two modes of Na channel modulation by PF-06526290 and that a single compound can affect sodium channel function in several ways.