Interaction with GM130 during HERG ion channel trafficking - Disruption by type 2 congenital long QT syndrome mutations

被引:56
作者
Roti, ECR
Myers, CD
Ayers, RA
Boatman, DE
Delfosse, SA
Chan, EKL
Ackerman, MJ
January, CT
Robertson, GA
机构
[1] Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA
[2] The Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[3] Mayo Clin & Mayo Fdn, Dept Internal Med, Div Cardiovasc Dis, Rochester, MN 55905 USA
[4] Mayo Clin & Mayo Fdn, Dept Pediat, Div Pediat Cardiol, Rochester, MN 55905 USA
[5] Mayo Clin & Mayo Fdn, Dept Mol Pharmacol, Rochester, MN 55905 USA
[6] Univ Wisconsin, Dept Med, Sect Cardiovasc Med, Madison, WI 53792 USA
关键词
D O I
10.1074/jbc.M206638200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Many mutations in the Human Ether-a-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.
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收藏
页码:47779 / 47785
页数:7
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