KCNQ1 and hERG encode the voltage-gated K+ channel α-subunits of the cardiac repolarizing currents IKs and IKr, respectively. These currents function in vivo with some redundancy to maintain appropriate action potential durations (APDs), following the concept of repolarization reserve, and mutations can manifest clinically as long QT syndrome, arrhythmia, and sudden cardiac death. Previous work in transgenic rabbit cardiomyocytes and heterologous cells demonstrated functional downregulation of complementary repolarizing currents due to direct interactions between hERG and KCNQ1 α-subunits, which may involve the hERG cyclic nucleotide binding domain (CNBD). We hypothesize that direct interactions between KCNQ1 and hERG are mediated by their C-termini and are dynamically regulated by physiological stimuli, specifically intracellular cAMP levels. We created ion channel fusions to GFP variants, which have been characterized by cellular electrophysiology and fluorescent imaging. Acceptor photobleach FRET (apFRET) was employed in fixed cells to quantitatively assess the extent of interactions based on fluorophore location and to examine the effects of altering cAMP levels. apFRET results show interactions between α-subunits with the highest FRET efficiency (Ef) for C-terminally labeled KCNQ1 and hERG (12.0 ± 5.2%), similar to intra-tetramer FRET, only between labeled hERG α-subunits (11.9 ± 5.9%). Acute treatment for 5 or 30 min. with Forskolin (100μM) + IBMX (100μM) significantly and specifically reduced Ef (7.1 ± 7.2% and 7.9 ± 4.3%, respectively, P < 0.001). Cells expressing a FRET positive control (KCNQ1-CFP-YFP) showed no change in Ef with treatment (21.4 ± 5.1% vs. 20.8 ± 5.6%, P=0.6). This work demonstrates regulated interactions between the C- termini of KCNQ1 and hERG, members of two distinct potassium channel families, and future studies will determine whether direct binding of cAMP abrogates KCNQ1-hERG interactions or if other downstream (PKA-mediated) processes are involved.