KCNQ1 and hERG encode the voltage-gated potassium channel α-subunits of the cardiac repolarizing currents I(Ks) and I(Kr), respectively. These currents function in vivo with some redundancy to maintain appropriate action potential durations (APDs), and loss-of-function mutations in these channels manifest clinically as long QT syndrome, characterized by the prolongation of the QT interval, polymorphic ventricular tachycardia, and sudden cardiac death. Previous cellular electrophysiology experiments in transgenic rabbit cardiomyocytes and heterologous cell lines demonstrated functional downregulation of complementary repolarizing currents. Biochemical assays indicated direct, protein-protein interactions between KCNQ1 and hERG may underlie the interplay between I(Ks) and I(Kr). Our objective was to investigate hERG-KCNQ1 interactions in the intact cellular environment primarily through acceptor photobleach FRET (apFRET) experiments. We quantitatively assessed the extent of interactions based on fluorophore location and the potential regulation of interactions by physiologically relevant signals. apFRET experiments established specific hERG-KCNQ1 associations in both heterologous and primary cardiomyocytes. The largest FRET efficiency (E(f); 12.0 ± 5.2%) was seen between ion channels with GFP variants fused to the COOH termini. Acute treatment with forskolin + IBMX or a membrane-permeable cAMP analog significantly and specifically reduced the extent of hERG-KCNQ1 interactions (by 41 and 38%, respectively). Our results demonstrate direct interactions between KCNQ1 and hERG occur in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini. Furthermore, this interplay between channel proteins is regulated by intracellular cAMP.

The central amygdala (CeA) is critically involved in a range of adaptive behaviors. In particular, the somatostatin-expressing (Sst + ) neurons in the CeA are essential for classic fear conditioning.These neurons send long-range projections to several extra-amygdala targets, but the functions of these projections remain elusive. Here, we found in mice that a subset of Sst + CeA neurons send projections to the globus pallidus external segment (GPe), and constitute essentially the entire GPe-projecting CeA population. Notably, chronic inhibition of GPe-projecting CeA neurons completely blocks auditory fear conditioning. These neurons are selectively excited by the unconditioned stimulus (US) during fear conditioning, and transient inactivation or activation of these neurons during US presentation impairs or promotes, respectively, fear learning. Our results suggest that a major function of Sst + CeA neurons is to represent and convey US information through the CeA-GPe circuit, thereby instructing learning in fear conditioning.(the "OFF" neurons) in response to cues predicting shocks. Such learning-induced changes in the responsiveness of CeA neurons to CS presentations may facilitate the expression of learned defensive responses, including conditioned freezing behavior (Ciocchi et al., 2010;Duvarci et al., 2011;Haubensak et al., 2010). These findings have led to the notion that the CeA, including the CeL, is essential for the formation of aversive memories.The CeA is a striatal-like structure that contains medium spiny neurons mainly derived from the lateral ganglionic eminence during development (

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