Regulation of Endocytic Recycling of KCNQ1/KCNE1 Potassium Channels

Abstract

Abstract-Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current, I Ks . KCNQ1 and KCNE1 subunits coassemble to form the I Ks channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death.Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum-and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P 2 . Identification of KCNQ1/KCNE1 recycling and its modulation by serum-and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P 2 provides a mechanistic insight into stress-induced acceleration of cardiac repolarization. (Circ Res. 2007;100:686-692.)Key Words: kinase Ⅲ PIP2 Ⅲ RAB Ⅲ trafficking Ⅲ PIKfyve E motional stress activates the sympathetic nervous system 1 and the release of stress hormones such as cortisol via the hypothalamic-pituitary-adrenal (HPA) axis 2 and is a common trigger of sudden cardiac death. 3,4 One of the many genes regulated by cortisol is the serum-and glucocorticoidinducible kinase 1 (SGK1). 5,6 In vitro experiments have shown that SGK1 stimulates I Ks 7 , a repolarizing potassium current conducted by channels composed of KCNQ1 ␣-subunits and KCNE1 ␤-subunits. 8,9 Moreover, a gain-offunction variant of SGK1 is associated with shortening of the QT interval. 10 SGK1-mediated regulation of I Ks might be particularly important in patients with KCNQ1 (Kv7.1, Kv-LQT1) or KCNE1 (minK) mutations that are prone to fatal cardiac arrhythmias triggered by physical and psychological stress. 4 The mechanism responsible for regulation of I Ks channels by SGK1 have remained elusive. SGK1 enhances the abundance of other types of channel protein in the plasma membrane by inhibiting the ubiquitin ligase Nedd4 -2 11 in addition to other mechanisms (summarized by Lang et al 2006 12 ).Other candidate signaling molecules that may affect channel trafficking include RAB family proteins, GTPases involved in vesicle cycling. [13][14][15][16][17][18] RAB5, a monomeric GTPase of the Ras superfamily, has been implicated in the regulation of early steps in the endocytic pathway, whereas the RAB11 GTPase is localized at the trans-Golgi network, post-Golgi vesicles and the recycling endosome. 19 Both RAB5 and RAB11 are expressed in cardiac tissue. 17 Mammalian cells and Xenopus laevis oocytes have been shown to possess and use highly conserved RAB-dependent trafficking pathways. 20,21 Endocytosis by RAB5 and exocytosis by RAB11 have been reported to participate in the regulation of CFTR chloride channels 22 and the glucose transporter GluT4. 15...

The Serum- and Glucocorticoid-inducible Kinases SGK1 and SGK3 Regulate hERG Channel Expression via Ubiquitin Ligase Nedd4-2 and GTPase Rab11

“…For the latter pathway, it has been reported that SGK phosphorylates and stimulates PIKfyve, a FYVE finger-containing phosphoinositide kinase that acts on phosphatidylinositol 3-phosphate to generate PI(3,5)P 2 (35). SGK-mediated activation of PIKfyve as well as addition of PI(3,5)P 2 to the cell have been shown to positively regulate Rab11-mediated insertion of KCNQ1/KCNE1 channels to the membrane (16).…”

“…Of interest is Rab11, which is highly expressed in cardiac myocytes (28) and is involved in the recycling/trafficking of various ion channels such as cystic fibrosis transmembrane conductance regulator chloride channels, Cav1.2 Ca 2ϩ channels, and the glucose transporter GluT4 (28 -30). In particular, SGK1 has been shown to increase the expression of the KCNQ1/KCNE1 (I Ks ) channel in the plasma membrane, and this increase is via the activation of a Rab11-mediated pathway (16).…”

“…Although SGK-mediated Nedd4-2 phosphorylation represents a mechanism for SGK to regulate ion channel expression levels, other mechanisms also exist. SGK increases the expression of the slowly activating delayed potassium current (I Ks ) through a Rab11-dependent pathway distinct from the Nedd4-2-mediated interaction (16). The study of effects of SGK1 and SGK3 on hERG has also been reported (17).…”

Identification of an Endocytosis Motif in an Intracellular Loop of Wntless Protein, Essential for Its Recycling and the Control of Wnt Protein Signaling

“…Endocytosis motifs in intracellular loops could have relevance to other multipass membrane proteins that undergo endocytosis, such as ion channels and G protein-coupled receptors (26,27). Whereas cytoplasmic tails can be readily inserted into chimeric reporter proteins for detailed analysis of endocytosis motifs (23), analyses of intracellular loops in isolation of the remainder of the membrane protein are more problematic because the structures of the intracellular loops are likely to be dependent on the correct membrane topology.…”

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

“…49 AQP2 is retrieved to early endosomes, and then transferred back to the Rab11-positive storage compartment. Thus, interference with Rab11 function might have unforeseen consequences, perturbing airway hindrance due to off-target effects on channels like AQP2 or potassium channels such as the potassiumvoltage-gated subfamily Q member 1 (KCNQ1) 50 or the voltage-dependent Kv1.5 51 whose recycling is also mediated by Rab11. Interestingly, a recent study described the cholesterol-lowering drugs statins, as potential potentiators of vasopressin-independent trafficking of AQP2 channels in the kidney.…”