Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Abstract

We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel ␣-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Electrophysiological remodeling in hypertrophy and heart failure predisposes the heart to lethal arrhythmias, which account for half of the mortality (1, 2). Experimental evidence derived from large scale clinical trials shows that inhibition of angiotensin II synthesis by inhibitors of angiotensin-converting enzyme or direct blockade of angiotensin receptor type 1 (AT1 1 receptor) with the antagonist losartan protects the heart from hypertensive complications (3, 4). A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11). Electrophysiologic remodeling affects the entire spectrum of cardiac ion channels including the transient outward potassium current (I to ) whose density is often decreased in heart failure (2, 12, 13).The mechanism of I to down-regulation in heart failure is not completely understood and is likely to have multiple etiologies. In part it can be explained by the inhibitory effects of angiotensin II. Experiments with spontaneously hypertensive rats suggest that the AT1 receptor might be directly involved in the regulation of I to . In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18). Distortion of the I to gradient leads to dispersion of repolarization across the ventricular wall, providing a substrate for ventricular arrhythmias (19). In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21-23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocar...

Mechanisms linking short- and long-term electrical remodeling in the heart .....is it a stretch?

“…Interestingly, it has also been reported that the angiotensin receptor interacts directly with K V 4.3 and modulates the gating and internalization of K V 4.3-encoded I to channels. 17 Taken together, these findings indicate a role for post-translational remodeling of Ca V and K V channels (possibly regulated through angiotensin) in short-term cardiac memory ( Fig. 2), with the additional involvement of Na V channel remodeling in human ventricles.…”

Renal Membrane Transport Proteins and the Transporter Genes

“…Angiotensin receptor forms a complex with potassium channel alphasubunit Kv 4.3 and regulates its intracellular distribution and gating properties [7]. Dihydropyridine Ca2+ channel antagonists / agonists may block Kv4.2, Kv4.3 and Kv1.4 K+ channels expressed in HEK293 cells [8].…”

Endocytic Regulation of Voltage-Dependent Potassium Channels in the Heart

“…Enhancement of the Kv4.3 current by tyrosine kinase is similar to KCNQ1 and opposite to Kv1.2 and Kv1.5. With respect to endocytosis, activation of AT 1 R was reported to suppress the Kv4.3 current through internalization of the receptor and channel complex (24). Kv4.3 has a β-subunit KChIP2 that enhances delivery of Kv4.3 to the cell surface.…”