Title: Nuclei have Heart: A hERG1 Channel Subdomain Targets the Nucleus
Abstract: hERG1NP, encoded by KCNH2, is a polypeptide expressed in the nuclei of developing cardiomyocytes. From the nucleus, hERG1NP activity reduces hERG1 current from the full-length hERG1 channel located at the cell’s surface membrane. The mechanisms regulating hERG1NP nuclear targeting have not been explored. Additionally, the impact of KCNH2 variants that map to hERG1NP have not been studied. We overexpressed wildtype and nuclear-targeting-deficient hERG1NP polypeptides in HEK293 cells to demonstrate that individual hERG1NP polypeptides heteromerize prior to entering the nucleus. Further, hERG1NP polypeptides carrying KCNH2 variants associated with sudden death, R1047L and Q1068R, altered hERG1NP nuclear targeting and subsequent regulation of the full-length channel. This work identifies mechanistic detail of hERG1NP function and demonstrates that KCNH2 variants associated with sudden death have the capacity to disrupt hERG1NP activity.
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