KvS regulatory subunits confer drug resistance to Kv2 channels.

KvS proteins are pore-forming voltage-gated potassium channel subunits that must co-assemble into heterotetramers with Kv2.1 ( KCNB1 ) or Kv2.2 ( KCNB2 ) subunits to form functional channels. In mammals, KvS subunits encompass the Kv5.1 ( KCNF1 ), Kv6.1 ( KCNG1 ), Kv6.2 ( KCNG2 ), Kv6.3 ( KCNG3 ), Kv6.4 ( KCNG4 ), Kv8.1 ( KCNV1 ), Kv8.2 ( KCNV2 ), Kv9.1 ( KCNS1 ), Kv9.2 ( KCNS2 ), and Kv9.3 ( KCNS3 ) proteins. While Kv2 proteins are broadly expressed in electrically excitable cells, KvS mRNAs are enriched in unique subsets of these cells. The physiological functions of KvS-containing channels are poorly understood and no drugs are known to selectively modulate KvS subunits. Here, we identify a pair of potent Kv2-selective inhibitors which distinguish conductances of KvS-containing channels. We find that conductances of KvS-containing channels are resistant to the pore-blocker RY785 yet remain sensitive to the voltage sensor modulator guangxitoxin-1E (GxTX). We show that this pattern of inhibitor sensitivities is consistent among subunits from Kv5, Kv6, Kv8, and Kv9 families. By deploying these inhibitors we find that mouse superior cervical ganglion neurons have conductances consistent with Kv2, but not KvS-containing channels. In contrast, mouse and human dorsal root ganglion neurons have conductances consistent with KvS/Kv2 heteromeric channels. These results provide an approach to pharmacologically distinguish KvS-containing from Kv2-only channels, and identify endogenous KvS conductances.