A K-TERMINAL DOMAIN REQUIRED FOR EXPRESSION OF RAPIDLY ACTIVATING DELAYED RECTIFIER CURRENT( CHANNEL SPLICE VARIANT COMMON IN HUMAN HEART LACKS A C)

We have cloned HERG(USO), a C-terminal splice variant of the human eth er-g-go-go-related gene (HERG), the gene encoding the rapid component of the delayed rectifier (I-Kr), from human heart, and we find that it s mRNA is similar to 2-fold more abundant than that for HERG(1) (the o riginally described cDNA). After transfection of HERG(USO) in Ltk(-) c ells, no current was observed, However, coexpression of HERG(USO) with HERG(1) modified I-Kr by decreasing its amplitude, accelerating its a ctivation, and shifting the voltage dependence of activation 8.8 mV ne gative. As with HERG(USO), HERG(Delta C) (a HERG(1), construct lacking the C-terminal 462 amino acids) also produced no current in transfect ed cells. However, I-Kr was rescued by ligation of 104 amino acids fro m the C terminus of HERG(1) to the C terminus of HERG(Delta C), indica ting that the C terminus of HERG(1) includes a domain (less than or eq ual to 104 amino acids) that is critical for faithful recapitulation o f I-Kr. The lack of this C-terminal domain not only explains the findi ng 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 a mplitude and gating of cardiac I-Kr depends on expression of both HERG (1) and HERG(USO).