Published online before print November 13, 2008, doi: 10.1161/CIRCRESAHA.108.177360
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2008 American Heart Association, Inc.
Cellular Biology |
Long QT Syndrome–Associated Mutations in KCNQ1 and KCNE1 Subunits Disrupt Normal Endosomal Recycling of IKs Channels
From the Department of Physiology I (G.S., N.S.-S., O.N.U., U.H., R.B., A.F.M., G.K., F.L.), University of Tuebingen, Germany; Department of Biochemistry I (G.S., N.S.-S., U.H., K.S., D.T.), Receptor Biochemistry, Ruhr University Bochum, Germany; Institute of Human Genetics (A.P., S.K.), Technical University Munich, Germany; Institute of Human Genetics (A.P., S.K.), National Research Center of Environment and Health, Neuherberg, Germany; Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (C.B.), Università di Lecce, Italy; Department of Physiology and Pharmacology (B.A.), Sackler Medical School, Tel Aviv University, Israel; INSERM U533 (J.M.), Institut du Thorax, Faculté de Médecine, Nantes, France; Department of Biochemistry (J.M.T.), School of Medical Sciences, University of Bristol, England; Department of Internal Medicine III (U.C.H.), Center for Molecular Medicine, University of Cologne, Germany; and Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute (M.C.S.), University of Utah, Salt Lake City.
Correspondence to Prof Dr Guiscard Seebohm, Biochemistry I, Cation Channel Group, Room NC6/132, Ruhr University Bochum, Universitätsstr. 150, D-44780 Bochum, Germany. E-mail guiscard.seebohm{at}gmx.de
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
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 IKs, a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in IKs channel
(KCNQ1, KvLQT1, Kv7.1) or β (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 IKs 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 IKs channels by SGK1 depends on residues H73, N75, D76, and P77 in KCNE1. Identification of the IKs recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress.
Key Words: kinase • trafficking • PIKfyve • LQT • stress
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Physical and emotional stress may trigger cardiac arrhythmia and sudden death in susceptible individuals.1–4 The stress reaction involves the release of stress hormones such as the glucocorticoid cortisol via the hypothalamic–pituitary–adrenal axis.5 Cortisol regulates the expression of several genes, including the serum- and glucocorticoid-inducible kinase (SGK)16,7 that is abundant in cardiac tissue.8 According to in vitro experiments SGK1 stimulates a slow delayed rectifier K+ current (IKs)9 that mediates cardiac repolarization. IKs is conducted by channels composed of KCNQ1
subunits and KCNE1 β subunits.10,11 SGK1 phosphorylates and thereby activates phosphoinositide 3-phosphate 5-kinase (PIKfyve), which generates PI(3,5)P2, which in turn enhances RAB11-dependent insertion of KCNQ1/KCNE1 (Q1/E1) channels into the plasma membrane.12 Accordingly, gain-of-function mutations of the genes encoding either SGK1 or Q1/E1 are associated with shortening of the QT interval, an electrocardiographic measure of ventricular repolarization time,13–15 whereas loss-of-function mutations lead to prolongation of the QT interval, causing long QT syndrome (LQTS). Here, we study the ability of SGK1 to recover loss-of-function LQTS mutant channels and determine the molecular requirements of SGK1 sensitivity. Stress-dependent stimulation of SGK1-mediated channel regulation might be of particular clinical importance for patients with KCNQ1 or KCNE1 mutations who are predisposed to potentially fatal cardiac arrhythmias triggered by physical and/or psychological stress.1,2 |
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Western Blot, Immunocytochemistry, and Molecular Biology
Western blot of plasma membrane proteins and molecular biology was performed as reported earlier.12 Cloning of RAB5, RAB7, RAB11, and FLAG-tagged KCNQ1 have been described previously.16–19 Further details are available in the online data supplement at http://circres.ahajournals.org.
Electrophysiology
Xenopus laevis oocytes were obtained according to German law as described previously.12 Ovary lobes were digested with collagenase (type II; Worthington), and stage 5 oocytes were collected and injected with 20 to 60 nL of cRNA. Oocytes were injected with 1 ng or 5 ng of KCNQ1 cRNA alone or with 1 ng KCNQ1 cRNA plus 1 ng of KCNE1 cRNA or 5 ng SGK1, RAB5/7/11 cRNA. Oocytes were stored for 3 to 4 days at 17°C in ND96 solution (in mmol/L: 96 NaCl, 4 KCl, 1.8 MgC12, 1.0 CaC12, 5 HEPES; and 50 mg/L gentamicin; pH 7.6). For voltage-clamp experiments the oocytes were bathed in ND96 solution. A TurboTEC-10 amplifier (npi electronic, Tamm, Germany) was used to record currents at 24°C in oocytes 3 to 4 days after injection with cRNA using standard 2-electrode voltage-clamp techniques. Data acquisition was performed using a Pentium IV computer, a Digidata 1322 A/D interface, and pClamp 8 software (Axon Instruments).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Structural Requirements for the Modulation of IKs Channels by SGK1
Previous experiments from our laboratory indicated that SGK1 enhances IKs by increasing the insertion of Q1/E1 channels into the plasma membrane.12 The effect did not require the presence of KCNE1 β subunits (Figure 1a). By contrast, deletion of the N-terminal residues 1 to 81 in KCNQ1 (resulting in KCNQ1
N-term) completely abolished the stimulation by SGK1 (Figure 1b). To determine whether a specific region of KCNE1 modulates SGK1-sensitive recycling, we deleted its intracellular C terminus. Deletion of the C-terminal residues 73 to 129 within KCNE1 (resulting in KCNE1C-term) abolished the stimulation of IKs by SGK1 (Figure 1b). Thus, the enhanced plasma membrane insertion of Q1/E1 channels depends on the presence of both the KCNQ1 N terminus and the KCNE1 C terminus. Further truncations identified the 7-aa stretch from residues 73 to 79 of KCNE1 as important for SGK1-dependent regulation of Q1/E1 channels (Figure 1c). Cysteine-scanning mutagenesis of this region identified residues crucial for SGK1 activation. When H73, N75, or D76 were mutated to Cys, coexpression of SGK1 had no effect or even reduced the current. By contrast, the P77C mutation facilitated the SGK1-mediated stimulation of IKs (Figure 1c). These results demonstrate the importance of the C-terminal HxNDP-containing region of KCNE1 for targeted Q1/E1 vesicular transport to the plasma membrane.
|
LQTS-Associated Mutations in KCNQ1 or KCNE1 Can Disrupt SGK1-Dependent Modulation of IKs
Next, we characterized the mechanism of SGK1-dependent modulation of several LQTS-associated mutant IKs channels. Two common LQTS-associated missense mutations in KCNE1 are located within the 73 to 79 region, namely S74L and D76N.20 To characterize the mechanism of SGK1-dependent modulation of these LQTS-associated mutant IKs channels we studied heteromeric channels coassembled of KCNQ1 and KCNE1(S74L) (Q1/S74L) or KCNE1(D76N) (Q1/D76N) subunits. Q1/S74L channels were activated by SGK1 (Figure 5), whereas currents mediated by Q1/D76N channels were reduced by SGK1 (Figure 2a). Changes in plasma membrane-associated KCNQ1 protein suggested that this functional reduction in mutant IKs was caused by a trafficking defect. SGK1 increased wild-type Q1/E1 but not Q1/D76N channel abundance in the plasma membrane, as assayed by Western blot and chemiluminescence analysis of surface protein (Figure 2b and 2c).12 Furthermore, a chemiluminescence assay of oocytes injected with cRNAs encoding Myc-tagged KCNQ1 and KCNE1(D76N) showed that constitutively active SGK1(S422D) but not inactive SGK1(K127N) decreased KCNQ1 protein in the plasma membrane (Figure 2c). In COS-7 cells cotransfected with Q1/D76N and SGK1(S422D), no increase in plasma membrane immunofluorescent staining of KCNQ1 was observed (Figure 2d). By contrast, we previously reported that constitutively active RAB11 increased plasma membrane abundance of heterologously expressed wild-type KCNQ1 protein in COS-7 cells.12
|
The small G proteins RAB5 and RAB11 are expressed in cardiac tissue and oocytes, where they constitute central components of recycling specificity and efficiency for vesicles containing wild-type IKs channels.12,20 RAB5 has been implicated in the regulation of early steps in the endocytic pathway, whereas RAB11 is localized at the trans-Golgi network, post-Golgi vesicles, and the recycling endosome.21 Hydrolysis of GTP activates RAB-dependent vesicle trafficking.16,22–26 The IKs recycling pathway can be assayed by injecting GTP into oocytes where RAB-dependent pathways are functionally impaired by overexpression of mutant forms of RAB5 and RAB11.12 Here, we used a similar approach to assay for the recycling pathway of mutant IKs channels. Oocytes expressing Q1/D76N channels were microinjected with GTP during voltage clamp, and ionic currents were recorded. Q1/D76N-mediated currents were increased by GTP when channels were coexpressed with dominant-negative RAB11(S25N) or the switch2 domain mutant RAB11(T77A).27 However, no change in Q1/D76N-mediated currents was noted when channels were coexpressed with GTP-insensitive RAB5(N133I) alone or in combination with either of the RAB11 mutants (Figure 3a). Wild-type IKs channels colocalize with RAB1112; however, using green fluorescent protein (GFP)-tagged KCNQ1 and DsRed-tagged RAB11 constructs, we observed no colocalization of RAB11 with Q1/D76N channels in COS-7 cells (Figure 3c). Taken together, these results indicate that Q1/D76N channels are endocytosed by RAB5 and reinserted into the plasma membrane by a RAB11-independent mechanism.
|
RAB7 is a protein that has been implicated in the regulation of late endosomal steps in the endocytic and lysosomal pathways.21 To understand where Q1/D76N channels accumulate in the cell, we coexpressed mutant channels with RAB7 and the dominant-negative RAB7 mutant T22N. RAB7(T22N) increased only Q1/D76N-mediated currents but not wild-type IKs (Figure 4a). According to chemiluminescence, coexpression of Q1/D76N channels with RAB7(T22N) increased the amount of Q1/D76N plasma membrane protein (Figure 4b). Cotransfection of wild-type and mutant Q1/E1 channels with RAB7(T22N) in COS-7 cells showed that Q1/D76N but not wild-type channels colocalize with RAB7-positive late endosomal vesicles (Figure 4c). These data suggest a close relationship of RAB7 with Q1/D76N but not wild-type channels.
|
To determine whether SGK1 modulates channels harboring a LQTS-associated mutation, we examined 8 previously characterized KCNQ1 mutants and the S74L mutant of KCNE1. Six of the 9 mutant channels were stimulated by coexpression with SGK1 (Figure 5). By contrast, Q1(P117L)/E1 channels were insensitive, and Q1(Y111C)/E1- and Q1(L114P)/E1-mediated currents were reduced by SGK1. These mutations were recently reported to disrupt normal trafficking.28 Interestingly, Q1(L114P) expressed without E1 was downregulated on SGK1 coexpression as well, suggesting that E1 is not required for the inversed SGK1 sensitivity (Figure I in the online data supplement). Like Q1/E1(D76N) channels, Q1(L114P)/E1 channels were modulated by RAB7(T22N) (Figure 4 and supplemental Figure II) and were mistargeted in transfected cardiomyocytes (supplemental Figure III).28 Furthermore, Q1(Y111C)/E1 and Q1(L114P)/E1 channels colocalized with RAB7 but not with RAB7(T22N) in COS7 cells (supplemental Figure IV). Similar to KCNE1, the KCNQ1 residues required for activation by SGK1 are located in an N-terminal juxtamembranous region.28 This raises the possibility that these regions of KCNQ1 and KCNE1 interact to promote trafficking of the heteromeric channel complex (Figure 5, inset).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In a previous study, we showed that SGK1 enhances the insertion of Q1/E1 channels into the plasma membrane.12 However, structural prerequisites have not been studied until now. The N terminus of KCNQ1 contains the important trafficking motif LEL and a critical tyrosine residue (Tyr51), both of which are required for Q1/E1 channel trafficking to basolateral membranes in MDCK cells.29 The LEL motif, as well as Tyr51, might be involved in the RAB5/11-dependent and SGK1-sensitive targeted recycling of IKs channels.12 Furthermore, the N terminus of KCNQ1 contains a PXXP sequence that may facilitate interactions with SH3 domains. Recently, direct interaction of the N terminus of KCNQ1 with β-tubulin in transfected COS-7 cells and in guinea pig cardiomyocytes was reported.30 Both the interaction with β-tubulin and the phosphorylation of Ser27 in KCNQ1 are prerequisites for protein kinase (PK)A-mediated activation of the channels.30,31 Interestingly, mutation of Ser27 or deletion of the N-terminal residues 1 to 81 in KCNQ1 (resulting in KCNQ1
N-term) disrupt its stimulation by SGK1 (Figure 1b and supplemental Figure V). These data raise the possibility that stimulations by SGK1 or PKA require both the integrity of a macromolecular complex and an intact interaction with the cytoskeleton.12,30,31 Misfolding of the β subunit KCNE1 as a result of deletion of the intracellular domain or of specific single amino acid substitutions might disturb the integrity of a macromolecular complex and/or cytoskeleton–KCNQ1 interactions, disrupting correct intracellular sorting to vesicles that are subject to SGK1-stimulated exocytosis. However, stimulation by SGK1 involves increased trafficking to the plasma membrane, whereas PKA-mediated stimulation of KCNQ1 seems not to be related to trafficking events.12,30 Here, we show that stimulation by SGK1 does not require the presence of KCNE1 β subunits (Figure 1a). However, when KCNE1 is present, a short stretch (73 to 79 region) within the KCNE1 intracellular C terminus is required for stimulation by SGK1 (Figure 1b and 1c). Within this region, we identified 4 residues (H73, N75, D76, and P77) that are critical for the normal effect of SGK1 on Q1/E1 channels (Figure 1c). These results indicate that the C-terminal juxtamembranous HxNDP-containing region of KCNE1 is important for targeted Q1/E1 vesicular transport to the plasma membrane. The intact intracellular KCNE1 C terminus was shown to interact with the sarcomeric protein T-cap, suggesting a T-tubule–myofibril linking system.32 Thus, Q1/E1 channel complexes contain several molecular components allowing for physical linkage to cytoskeletal compartments, which may allow specific and efficient trafficking along the cytoskeleton (Figure 1d). Two common LQTS-associated missense mutations in KCNE1 are located within the 73 to 79 region, namely S74L and D76N.33 Q1/S74L channels were activated by SGK1 (Figure 5), whereas Q1/D76N-mediated currents were reduced by active SGK1 (Figure 2a) possibly as a result of reduced plasma membrane-associated KCNQ1 protein as demonstrated by Western blot and chemiluminescence analysis of surface protein (Figure 2b and 2c).12 By analysis of 9 previously characterized LQT1 mutants, we identified 6 mutant channels that were stimulated by coexpression with SGK1 (Figure 5). By contrast, 3 mutant channels were either insensitive or inhibited by SGK1. These 3 mutations (P117L, Y111C, and L114P in KCNQ1) were recently reported to disrupt normal trafficking.28 We previously reported that constitutively active SGK1 increased plasma membrane abundance of heterologously expressed wild-type KCNQ1 protein in COS-7 cells.12 This effect is absent in COS-7 cells cotransfected with Q1/D76N and constitutively active SGK1(S422D) (Figure 2d). Thus, the SGK1-stimulated plasma membrane insertion of Q1/E1 is disrupted in several LQT1 mutant channels and 1 LQT5 mutant Q1/E1 channel. Similar to KCNE1, the KCNQ1 residues required for activation by SGK1 are located in an N-terminal juxtamembranous region.28 This raises the possibility that these regions of KCNQ1 and KCNE1 interact to promote trafficking of the heteromeric channel complex (Figure 5, inset).
RAB5 has been implicated in the regulation of early steps in the endocytic pathway, whereas RAB11 is localized at the trans-Golgi network, post-Golgi vesicles, and the recycling endosome.21 The D76N mutation in KCNE1 uncouples IKs channels from normal RAB11-dependent endosome recycling to the plasma membrane and induces a distinct, RAB11-independent recycling pathway (Figure 3a). On the contrary, wild-type IKs channels colocalize with RAB11.12 Taken together, these results indicate that Q1/D76N channels are endocytosed by RAB5 and reinserted into the plasma membrane by a RAB11-independent mechanism. The lack of acute functional effects of RAB11(S25N) or RAB11(T77A) (Figure 3a) and the lack of colocalization with RAB11 (Figure 3b) suggest that RAB11-dependent vesicle recycling to the plasma membrane might be disrupted in Q1/D76N channels. Consequently, Q1/D76N channels may escape RAB11-dependent recycling, and formation of storage vesicles (as was observed for wild-type IKs channels) may be compromised.
RAB7 is a protein implicated in the regulation of late endosomal steps in the endocytic and lysosomal pathways.21 The dominant-negative RAB7 mutant T22N increased only Q1/D76N-mediated currents but not wild-type IKs (Figure 4a) by increasing the amount of Q1/D76N plasma membrane protein (Figure 4b). Like Q1/E1(D76N) channels, Q1(L114P)/E1 channels were modulated by RAB7(T22N) (Figure 4 and supplemental Figure II). Furthermore, cotransfection of wild-type and mutant Q1/E1 channels with RAB7(T22N) in COS-7 cells showed that Q1/D76N but not wild-type channels colocalize with RAB7-positive late endosomal vesicles (Figure 4c). Furthermore, Q1(Y111C)/E1 and Q1(L114P)/E1 channels colocalize with RAB7 but not with RAB7(T22N) in COS7 cells (supplemental Figure IV). Three findings suggest that the disease-associated mutant channels may be stored in late endosomes and possibly the endoplasmic reticulum (ER): (1) Q1/D76N channels do not colocalize with RAB11 and can be trafficked back to the plasma membrane by a GTP-dependent but RAB11-independent process (Figure 3a and 3c); (2) Q1/D76N channels [and Q1(Y111C)/E1 and Q1(L114P)/E1 channels] colocalize in an intracellular compartment with RAB7 and are modulated by RAB7(T22N) (Figure 4); and (3) SGK1 treatment does not result in additional fractional bands in Western blots, indicating that Q1/D76N channels are not trafficked to lysosomes and digested by enzymes.
SGK1-mediated phosphorylation of PIKfyve and subsequent PI(3,5)P2 production act to regulate channel activity via RAB11-dependent vesicle exocytosis (Figure 6). Taken together, our findings suggest that Q1/D76N, Q1(Y111C)/E1, and Q1(L114P)/E1 channels are trafficked forward to RAB7-dependent late endosomal vesicles and/or the endoplasmic reticulum. Indeed, Q1(Y111C)/E1 and Q1(L114P)/E1 were reported to be enriched in the ER.28 The localization of KCNE1(D76N) seems to be altered in stem cell–derived ventricular myocytes as well (supplemental Figure V). An altered localization of Q1(Y111C)/E1, Q1(L114P)/E1, and Q1(P117L)/E1 channels has been reported for cardiac myocytes.28 Stimulation of RAB11-dependent exocytosis will result in increased endocytosis of plasma membrane containing mutant Q1/E1 channels, reducing channel density in the plasma membrane and thereby current amplitudes (Figure 6). Mutant channels stored in late endosomes, ER, and possibly Golgi apparatus can potentially be trafficked to the plasma membrane, and stimulation of this ER export forward trafficking by GTP would explain the RAB11-independent stimulation of Q1/D76N-mediated currents (Figure 3a).
|
The present findings bear potential clinical significance. Carriers of the E1(D76N), Q1(Y111C), or Q1(L114P) mutations may benefit from avoidance of situations (eg, sustained stress, dexamethasone treatment, and excessive blood insulin levels) that might stimulate SGK1 and lead to an even greater decrease in IKs and prolongation of QT intervals.
In summary, our studies demonstrate a link between altered vesicle recycling of disease-associated mutant IKs channels and the stress-dependent kinase SGK1.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported by the Deutsche Forschungsgemeinschaft (La315/4-5 and SFB), a stipend from the Gottlieb Daimler-und Karl Benz-Stiftung (to G.S.), a stipend from the Erwin-Riesch-Stiftung (to G.S.) and MIUR-PRIN2004 (to C.B.), and a Deutsche Forschungsgemeinschaft stipend (GRK 1302/1) (to U.H.). S.K. was funded by German National Genome Research Network grant 01GS0838 and the Leducq Fondation.
Disclosures
None.
|
Footnotes |
|---|
This manuscript was sent to Harry Fozzard, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Original received August 14, 2007; resubmission received April 8, 2008; revised resubmission received October 9, 2008; accepted November 3, 2008.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Eliot RS, Buell JC. Role of emotions and stress in the genesis of sudden death. J Am Coll Cardiol. 1985; 5: 95B–98B.[Medline] [Order article via Infotrieve]
2. Schwartz PJ, Zaza A, Locati E, Moss AJ. Stress and sudden death. The case of the long QT syndrome. Circulation. 1991; 83 (suppl II): II-71–II-80.[Medline] [Order article via Infotrieve]
3. Paavonen KJ, Swan H, Piippo K, Hokkanen L, Laitinen P, Viitasalo M, Toivonen L, Kontula K. Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome. Heart. 2001; 86: 39–44.
4. Towbin JA, Wang Z, Li H. Genotype and severity of long QT syndrome. Drug Metab Dispos. 2001; 29: 574–579.
5. Kern W, Perras B, Wodick R, Fehm HL, Born J. Hormonal secretion during nighttime sleep indicating stress of daytime exercise. J Appl Physiol. 1995; 79: 1461–1468.
6. Lang F, Cohen P. Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci STKE. 2001; 2001: RE17.[Medline] [Order article via Infotrieve]
7. Lang F, Henke G, Embark HM, Waldegger S, Palmada M, Bohmer C, Vallon V. Regulation of channels by the serum and glucocorticoid-inducible kinase - implications for transport, excitability and cell proliferation. Cell Physiol Biochem. 2003; 13: 41–50.[CrossRef][Medline] [Order article via Infotrieve]
8. Waldegger S, Barth P, Raber G, Lang F. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc Natl Acad Sci U S A. 1997; 94: 4440–4445.
9. Embark HM, Böhmer C, Vallon V, Luft F, Lang F. Regulation of KCNE1 dependent K+current by the serum and glucocorticoid-inducible kinase (SGK) isoforms. Pflugers Arch. 2003; 445: 601–606.[Medline] [Order article via Infotrieve]
10. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature. 1996; 384: 78–80.[CrossRef][Medline] [Order article via Infotrieve]
11. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996; 384: 80–83.[CrossRef][Medline] [Order article via Infotrieve]
12. Seebohm G, Strutz-Seebohm N, Birkin R, Dell G, Bucci C, Spinosa MR, Baltaev R, Mack AF, Korniychuk G, Choudhury A, Marks D, Pagano RE, Attali B, Pfeufer A, Kass RS, Sanguinetti MC, Tavare JM, Lang F. Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ Res. 2007; 100: 686–692.
13. Busjahn A, Seebohm G, Maier G, Toliat MR, Nurnberg P, Aydin A, Luft FC, Lang F. Association of the serum and glucocorticoid regulated kinase (sgk1) gene with QT interval. Cell Physiol Biochem. 2004; 14: 135–142.[CrossRef][Medline] [Order article via Infotrieve]
14. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003; 299: 251–254.
15. Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P, Sachse F, Sanguinetti MC, Brugada R. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res. 2005; 68: 433–440.
16. Hoekstra D, Tyteca D, Van IJzendoorn SC. The subapical compartment: a traffic center in membrane polarity development. J Cell Sci. 2004; 117: 2183–2192.
17. Choudhury A, Dominguez M, Puri V, Sharma DK, Narita K, Wheatley CL, Marks DL, Pagano RE. Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. J Clin Invest. 2002; 109: 1541–1550.[CrossRef][Medline] [Order article via Infotrieve]
18. Sharma DK, Choudhury A, Singh RD, Wheatley CL, Marks DL, Pagano RE. Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J Biol Chem. 2003; 278: 7564–7572.
19. Kanki H, Kupershmidt S, Yang T, Wells S, Roden DM. A structural requirement for processing the cardiac K+ channel KCNQ1. J Biol Chem. 2004; 279: 33976–33983.
20. Kessler A, Tomas E, Immler D, Meyer HE, Zorzano A, Eckel J. Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin. Diabetologia. 2000; 43: 1518–1527.[CrossRef][Medline] [Order article via Infotrieve]
21. Grosshans BL, Ortiz D, Novick P. Rabs and their effectors: achieving specificity in membrane traffic. Proc Natl Acad Sci U S A. 2006; 103: 11821–11827.
22. Marks DL, Pagano RE. Endocytosis and sorting of glycosphingolipids in sphingolipid storage disease. Trends Cell Biol. 2002; 12: 605–613.[CrossRef][Medline] [Order article via Infotrieve]
23. Maxfield FR, McGraw TE. Endocytic recycling. Nat Rev Mol Cell Biol. 2004; 5: 121–132.[CrossRef][Medline] [Order article via Infotrieve]
24. Prekeris R. Rabs, Rips, FIPs, and endocytic membrane traffic. Sci World J. Available at: http://www.ncbi.nlm.nih.gov/sites/entrez.
25. Ullrich O, Horiuchi H, Bucci C, Zerial M. Membrane association of Rab5 mediated by GDP-dissociation inhibitor and accompanied by GDP/GTP exchange. Nature. 1994; 368: 157–160.[CrossRef][Medline] [Order article via Infotrieve]
26. Pasqualato S, Senic-Matuglia F, Renault L, Goud B, Salamero J, Cherfils J. The structural GDP/GTP cycle of Rab11 reveals a novel interface involved in the dynamics of recycling endosomes. J Biol Chem. 2004; 279: 11480–11488.
27. Pfeffer SR. Structural clues to Rab GTPase functional diversity. J Biol Chem. 2005; 280: 15485–15488.
28. Dahimene S, Alcolea S, Naud P, Jourdon P, Escande D, Brasseur R, Thomas A, Baro I, Merot J. The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome. Circ Res. 2006; 99: 1076–1083.
29. Jespersen T, Rasmussen HB, Grunnet M, Jensen HS, Angelo K, Dupuis DS, Vogel LK, Jorgensen NK, Klaerke DA, Olesen SP. Basolateral localization of KCNQ1 potassium channels in MDCK cells: molecular identification of an N-terminal targeting motif. J Cell Sci. 2004; 117: 4517–4526.
30. Nicolas CS, Park KH, El Harchi A, Camonis J, Kass RS, Escande D, Mérot J, Loussouarn G, Le Bouffant F, Baró I. IKs response to protein kinase A-dependent KCNQ1 phosphorylation requires direct interaction with microtubules. Cardiovasc Res. 2008; 79: 427–435.
31. Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, Kass RS. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002; 295: 496–499.
32. Furukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, et al. Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system. J Mol Biol. 2001; 313: 775–784.[CrossRef][Medline] [Order article via Infotrieve]
33. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997; 17: 338–340.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  G. M. Marcus, E. Keung, and M. M. Scheinman The year in review of clinical cardiac electrophysiology. J. Am. Coll. Cardiol., August 25, 2009; 54(9): 777 - 787. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schulze-Bahr Making sense in a nonsense reading frame: suppression of cardiac sodium channel dysfunction Cardiovasc Res, August 1, 2009; 83(3): 423 - 424. [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. H. Mauban, M. O'Donnell, S. Warrier, S. Manni, and M. Bond AKAP-Scaffolding Proteins and Regulation of Cardiac Physiology Physiology, April 1, 2009; 24(2): 78 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. McEwen and J. R. Martens Antifibrillatory Agents and Potassium Channels in the Atria: Pore Block versus Channel Trafficking Mol. Interv., April 1, 2009; 9(2): 79 - 86. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||