The human ERG protein (HERG or Kv 11.1) encoded by the human 
ether-a-go-go-related gene (herg) is the pore-forming subunit of the cardiac 
delayed rectifier potassium current (IKr) responsible for action potential (AP) 
repolarization. Mutations in HERG lead to long-QT syndrome, a major cause of 
arrhythmias. Protein-protein interactions are fundamental for ion channel 
trafficking, membrane localization, and functional modulation. To identify 
proteins involved in the regulation of the HERG channel, we conducted a yeast 
two-hybrid screen of a human heart cDNA library using the C-terminus or 
N-terminus of HERG as bait. Fifteen proteins were identified as HERG amino 
terminal (HERG-NT)-interacting proteins, including Caveolin-1 (a membrane 
scaffold protein with multiple interacting partners, including G-proteins, 
kinases and NOS), the zinc finger protein, FHL2 and PTPN12 (a non-receptor 
tyrosine phosphatase). Eight HERG carboxylic terminal (HERG-CT)-interacting 
proteins were also identified, including the NF-κB-interacting protein 
myotrophin, We have identified multiple potential interacting proteins that may 
regulate cardiac IKr through cytoskeletal interactions, G-protein modulation, 
phosphorylation and downstream second messenger and transcription cascades. 
These findings provide further insight into dynamic modulation of HERG under 
physiological conditions and arrhythmogenesis.