Long QT Syndrome–Associated Mutations in KCNQ1 and
KCNE1 Subunits Disrupt Normal Endosomal Recycling of
IKs Channels
by Guiscard Seebohm, Nathalie Strutz-Seebohm, Oana N. Ureche, Ulrike Henrion,
Ravshan Baltaev, Andreas F. Mack, Ganna Korniychuk, Katja Steinke, Daniel
Tapken, Arne Pfeufer, Stefan Kääb, Cecilia Bucci, Bernard Attali, Jean Merot, Jeremy
M. Tavare, Uta C. Hoppe, Michael C. Sanguinetti, and Florian Lang
Circulation Research
Volume 103(12):1451-1457
December 5, 2008
Copyright © American Heart Association, Inc. All rights reserved.
Figure 1. Deletion of the KCNQ1 N terminus and disruption of a motif in KCNE1 impair SGK1dependent stimulation. a, KCNQ1 (Q1) channels are stimulated when coexpressed with SGK1 in
oocytes.
Guiscard Seebohm et al. Circ Res. 2008;103:1451-1457
Copyright © American Heart Association, Inc. All rights reserved.
Figure 2. SGK1 decreases Q1/D76N current density by reducing plasma membrane abundance of
the channels. a, KCNQ1 was coexpressed with KCNE1 carrying the LQTS-associated mutation
D76N, which is localized in the region important for SGK1 effects.
Guiscard Seebohm et al. Circ Res. 2008;103:1451-1457
Copyright © American Heart Association, Inc. All rights reserved.
Figure 3. Q1/E1(D76N) is endocytosed by a RAB5-dependent and recycled back to the plasma
membrane by a RAB11-independent SGK1-sensitive pathway. a, Q1/D76N expressed alone, with
GTP binding–insufficient RAB5(N133I), with dominant-negative RAB11(S25N), with switch2
domain mutant RAB11(T77A), or with combinations of the constructs.
Guiscard Seebohm et al. Circ Res. 2008;103:1451-1457
Copyright © American Heart Association, Inc. All rights reserved.
Figure 4. RAB7 modulates current density and plasma membrane abundance of Q1/E1(D76N)
channels. a, Q1/E1 and Q1/D76N were expressed in oocytes in the absence or presence of either
wild-type RAB7 or the dominant-negative mutant RAB7(T22N).
Guiscard Seebohm et al. Circ Res. 2008;103:1451-1457
Copyright © American Heart Association, Inc. All rights reserved.
Figure 5. Differential SGK1 sensitivity of Q1/E1 channels containing LQTS1-associated
mutations.
Guiscard Seebohm et al. Circ Res. 2008;103:1451-1457
Copyright © American Heart Association, Inc. All rights reserved.
Figure 6. Diagram of Q1/E1 and Q1/D76N channel recycling.
Guiscard Seebohm et al. Circ Res. 2008;103:1451-1457
Copyright © American Heart Association, Inc. All rights reserved.