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The three members of the  ether-à-go-go-gene -like (Elk; K v 12.1-K v 12.3) family of voltage-gated K +  channels are predominantly expressed in neurons, but only little information is available on their physiological relevance. It was shown that K v 12.2 channels modulate excitability of hippocampal neurons, but no native current could be attributed to K v 12.1 and K v 12.3 subunits yet. This may appear somewhat surprising, given high expression of their mRNA transcripts in several brain areas. Native K v 12 currents may have been overlooked so far due to limited knowledge on their biophysical properties and lack of specific pharmacology. Except for K v 12.2, appropriate genetically modified mouse models have not been described; therefore, identification of K v 12-mediated currents in native cell types must rely on characterization of unique properties of the channels. We focused on recombinant human K v 12.1 to identify distinct properties of these channels. We found that K v 12.1 channels exhibited significant mode shift of activation, i.e., stabilization of the voltage sensor domain in a “relaxed” open state after prolonged channel activation. This mode shift manifested by a slowing of deactivation and, most prominently, a significant shift of voltage dependence to hyperpolarized potentials. In contrast to related K v 11.1, mode shift was not sensitive to extracellular Na + , which allowed for discrimination between these isoforms. Sensitivity of K v 12.1 and K v 11.1 to the broad-spectrum K +  antagonist 4-aminopyridine was similar. However, 4-AP strongly activated K v 12.1 channels, but it was an inhibitor of K v 11 channels. Interestingly, the agonist of K v 11 channels NS1643 also differentially modulated the activity of these channels, i.e., NS1643 activated K v 11.1, but strongly inhibited K v 12.1 channels. Thus, these closely related channels are distinguished by inverse pharmacological profiles. In summary, we identified unique biophysical and pharmacological properties of K v 12.1 channels and established straightforward experimental protocols to characterize K v 12.1-mediated currents. Identification of currents in native cell types with mode shift that are activated through 4-AP and inhibited by NS1643 can provide strong evidence for contribution of K v 12.1 to whole cell currents.

Inverse Modulation of Neuronal Kv12.1 and Kv11.1 Channels by 4-Aminopyridine and NS1643