Defective protein trafficking of HERG K⁺ channels in human congenital long QT syndrome

It is now clear that LQT2 represents a large number of mutations throughout the HERG channel protein that cause a decrease in I_Kr amplitude to increase in the QT interval. At least for LQT2, this is a disease of increasing complexity that depends on many mechanisms involving abnormalities in HERG protein processing and trafficking, HERG channel function and subunit co-assembly that vary from one mutation to the next. In a simplified form this is shown in Figure 5. For many LQT2 mutations, the dominant mechanism appears to be retention and degradation of abnormal protein in the endoplasmic reticulum and its failure to traffic to the plasma, even if the channel is capable of functioning biophysically. Thus, in patients the emerging data support the concept that it is the interaction of several mechanisms that determines I_Kr properties, and contributes to the variable expression and severity of the LQT2 phenotype. As our understanding of these mechanisms and their interactions increases, this offers the potential for new therapeutic approaches.