A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current

Abstract

We have cloned HERG(USO), a C-terminal splice variant of the human ether-a-go-go-related gene (HERG), the gene encoding the rapid component of the delayed rectifier (I(Kr)), from human heart, and we find that its mRNA is ~2-fold more abundant than that for HERG1 (the originally described cDNA). After transfection of HERG(USO) in Ltk- cells, no current was observed. However, coexpression of HERG(USO) with HERG1 modified I(Kr) by decreasing its amplitude, accelerating its activation, and shifting the voltage dependence of activation 8.8 mV negative. As with HERG(USO), HERG(ΔC) (a HERG1 construct lacking the C-terminal 462 amino acids) also produced no current in transfected cells. However, I(Kr) was rescued by ligation of 104 amino acids from the C terminus of HERG1 to the C terminus of HERG(ΔC), indicating that the C terminus of HERG1 includes a domain (≤104 amino acids) that is critical for faithful recapitulation of I(Kr). The lack of this C-terminal domain not only explains the finding that HERG(USO) does not generate I(Kr) but also indicates a similar mechanism for hitherto- uncharacterized long QT syndrome HERG mutations that disrupt the splice site or the C-terminal. We suggest that the amplitude and gating of cardiac I(Kr) depends on expression of both HERG1 and HERG(USO).