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PF‐06526290 can both enhance and inhibit conduction through voltage‐gated sodium channels
Author(s) -
Wang Lingxin,
Zellmer Shan G,
Printzenhoff David M,
Castle Neil A
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14338
Subject(s) - sodium channel , depolarization , gating , biophysics , electrophysiology , chemistry , ion channel , sodium , voltage gated ion channel , membrane potential , biochemistry , neuroscience , biology , receptor , organic chemistry
Background and Purpose Pharmacological agents that either inhibit or enhance flux of ions through voltage‐gated sodium (Na v ) channels may provide opportunities for treatment of human health disorders. During studies to characterize agents that modulate Na v 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 v channel function. Key Results PF‐06526290 greatly slows inactivation of Na v channels in a subtype‐independent manner. However, upon prolonged depolarization to induce inactivation, PF‐06526290 becomes a Na v subtype‐selective inhibitor. Mutation of the domain 4 voltage sensor modulates inhibition of Na v 1.3 or Na v 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 v channel modulation by PF‐06526290 and that a single compound can affect sodium channel function in several ways.