Abstract
hERG1(NP) is a non-conducting subdomain of the full-length hERG1 channel that is expressed in the nuclei of developing cardiomyocytes. From the nucleus, hERG1(NP) modulates gating and expression of the full-length hERG1 channel. hERG1(NP) variants are linked with sudden death in the young, but the impact of these variants on hERG1(NP) activity has not been studied. To determine the effect of hERG1(NP) variants on hERG1(NP) activity, we measured hERG1(NP) intracellular localization and modulation of membrane current from the full-length hERG1a channel in HEK293 cells. The wildtype hERG1(NP) suppressed both hERG1a current (I (hERG)) and protein. We then screened six hERG1(NP) variants for changes in either intracellular targeting or modulation of hERG1a current. Two variants, R885C and R1047L, disrupted hERG1(NP) activity by altering nuclear transport or abolishing both I (hERG) current suppression and nuclear targeting, respectively. Two additional variants, G1036D and Q1068R, enhanced hERG1(NP) activity by depolarizing hERG1a's voltage dependence of activation via accelerated channel deactivation and recovery from inactivation. Lastly, two variants had no effect: R1035W and R1069S. This work demonstrates that hERG1(NP) variants associated with sudden death in the young can trigger both loss-of-function and gain-of-function effects on hERG1(NP). Additional work is needed to identify specific pathogenic mechanisms of hERG1(NP) variants.