Long QT Syndrome-Associated Mutations in KCNQ1 and KCNE1 Subunits Disrupt Normal Endosomal Recycling of IKs Channels

Department of Physiology I, University of Tuebingen, Germany.
Circulation Research (Impact Factor: 11.02). 12/2008; 103(12):1451-7. DOI: 10.1161/CIRCRESAHA.108.177360
Source: PubMed


Physical and emotional stress is accompanied by release of stress hormones such as the glucocorticoid cortisol. This hormone upregulates the serum- and glucocorticoid-inducible kinase (SGK)1, which in turn stimulates I(Ks), a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in I(Ks) channel alpha (KCNQ1, KvLQT1, Kv7.1) or beta (KCNE1, IsK, minK) subunits cause long QT syndrome (LQTS), an inherited cardiac arrhythmia associated with increased risk of sudden death. Together with the GTPases RAB5 and RAB11, SGK1 facilitates membrane recycling of KCNQ1 channels. Here, we show altered SGK1-dependent regulation of LQTS-associated mutant I(Ks) channels. Whereas some mutant KCNQ1 channels had reduced basal activity but were still activated by SGK1, currents mediated by KCNQ1(Y111C) or KCNQ1(L114P) were paradoxically reduced by SGK1. Heteromeric channels coassembled of wild-type KCNQ1 and the LQTS-associated KCNE1(D76N) mutant were similarly downregulated by SGK1 because of a disrupted RAB11-dependent recycling. Mutagenesis experiments indicate that stimulation of I(Ks) channels by SGK1 depends on residues H73, N75, D76, and P77 in KCNE1. Identification of the I(Ks) recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress.

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    • "This being stated, KCNE1 effects could also involve other pathways for internalization, such as caveolae in lipid rafts, which also utilize dynamin, or ubiquitylation. The aspartate residue in the DPFNVY motif, D76, has been found by Seebohm et al. (2008) to be important for Rab 5 mediated internalization of KCNQ1-KCNE1 complexes in Xenopus oocytes. This residue is also the site of a LQTS mutation, D76N, which has a strong dominant-negative effect on IKs currents, significantly decreasing IKs current density (Splawski et al., 1997; Hoppe et al., 2001). "
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    Preview · Article · Jun 2012 · Frontiers in Physiology
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    • "The ß-catenin protein generated by translation from the injected mRNA could, in theory, enter the nucleus of the oocytes and modulate expression of endogenous genes as transcription factor. For instance, ß-catenin could stimulate I Ks by upregulating the expression of SGK1 (Naishiro et al. 2005, Dehner et al. 2008) and subsequent stimulation of KCNE1/KCNQ1 by SGK1 (Busjahn et al. 2004, Seebohm et al. 2008, Strutz-Seebohm et al. 2009). Xenopus oocytes do express an endogenous SGK1 (Sopjani et al. 2010b). "
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    • "In the heart the KCNQ1–E1 complex conducts the delayed rectifier current I KS (Barhanin et al. 1996). KCNE-mediated current (I KS ) plays a critical role in repolarisation of cardiac myocytes, and mutations in Q1 or E1 cause some forms of long QT syndrome, a disease associated with prolonged cardiac action potentials and an increased risk of sudden death (Seebohm et al. 2008). KCNQ1–E1-mediated forms of long QT syndrome are also associated with deafness, as the channel complex also plays a critical role in the formation of the K + -rich endolymph in the ear (Casimiro et al. 2001). "
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