Inverse Modulation of Neuronal K(v)12.1 and K(v)11.1 Channels by 4-Aminopyridine and NS1643

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.