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J. Biol. Chem., Vol. 277, Issue 49, 47779-47785, December 6, 2002
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From the Many mutations in the Human
Ether-à-go-go-Related Gene (HERG) cause type 2 congenital long QT syndrome (LQT2) by disrupting trafficking of the
HERG-encoded potassium channel. Beyond observations that
some mutations trap channels in the endoplasmic reticulum, little is
known about how trafficking fails. Even less is known about what
checkpoints are encountered in normal trafficking. To identify protein
partners encountered as HERG channels are transported among subcellular
compartments, we screened a human heart library with the C terminus of
HERG using yeast two-hybrid technology. Among the proteins isolated was
GM130, a Golgi-associated protein involved in vesicular transport. The
interaction mapped to two non-contiguous regions of HERG and to a
region just upstream of the GRASP-65 interaction domain of GM130. GM130
did not interact with the N or C terminus of either KvLQT1 or Shaker
channels. LQT2-causing mutations in the HERG C terminus selectively
disrupted interactions with GM130 but not Tara, another
HERG-interacting protein. Native GM130 and stably expressed HERG were
co-immunoprecipitated from HEK-293 cells using GM130 antibodies. In rat
cardiac myocytes and HEK-293 cells, confocal immunocytochemistry showed
co-localization of GM130 and HERG to the Golgi apparatus.
Overexpression of GM130 suppressed HERG current amplitude in
Xenopus oocytes, as if by providing an excess of substrate
at the Golgi checkpoint. These findings indicate that GM130 plays a
previously undefined role in cargo transport. We propose that the
cytoplasmic C terminus of HERG participates in the tethering or
possibly targeting of HERG-containing vesicles within the Golgi via its
interaction with GM130.
Interaction with GM130 during HERG Ion Channel Trafficking
DISRUPTION BY TYPE 2 CONGENITAL LONG QT SYNDROME MUTATIONS*
,§,,,,
,**, and
Department of Physiology, University of
Wisconsin, Madison, Wisconsin 53706, the ¶ Department of
Molecular and Experimental Medicine, The Scripps Research Institute,
La Jolla, California 92037, the Departments of Internal
Medicine, Pediatrics, and Molecular Pharmacology, Divisions of
Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic/Mayo
Foundation, Rochester, Minnesota 55905, and ** Section of
Cardiovascular Medicine, the Department of Medicine, University of
Wisconsin, Madison, Wisconsin 53792
*
This work was supported by a Howard Hughes Medical
Institutes-University of Wisconsin-Madison Medical School Faculty
Development award and National Institutes of Health Grant R01-HL68868
and in part by a National Science Foundation Career award and National Institutes of Health R01-HL55973 (to G. A. R.), a Clinical Scientist Development award from the Doris Duke Charitable Foundation (to M. J. A.), and National Institutes of Health Grant R01-HL60723 (to
C. T. J.). This work was originally presented in abstract form (Roti
Roti, E. C., Myers, C. D., Ayers, R. A., Boatman,
D. E., January, C. T., and Robertson, G. A. (2001)
Mol. Biol. Cell 12, 2577).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Physiology, University of Wisconsin, 1300 University Ave., Madison, WI 53706. Tel.: 608-265-3339; E-mail:
robertson@physiology.wisc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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