PMID- 26718903
OWN - NLM
STAT- MEDLINE
DCOM- 20170918
LR  - 20181113
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 594
IP  - 9
DP  - 2016 May 1
TI  - hERG quality control and the long QT syndrome.
PG  - 2469-81
LID - 10.1113/JP270531 [doi]
AB  - Long-QT syndrome type-2 (LQT2) is characterized by reduced functional expression 
      of the human ether-a-go-go related (hERG) gene product, resulting in impaired 
      cardiac repolarization and predisposition to fatal arrhythmia. Previous studies 
      have implicated abnormal trafficking of misfolded hERG as the primary mechanism 
      of LQT2, with misfolding being caused by mutations in the hERG gene (inherited) 
      or drug treatment (acquired). More generally, environmental and metabolic 
      stresses present a constant challenge to the folding of proteins, including hERG, 
      and must be countered by robust protein quality control (QC) systems. Disposal of 
      partially unfolded yet functional plasma membrane (PM) proteins by protein QC 
      contributes to the loss-of-function phenotype in various conformational diseases 
      including cystic fibrosis (CF) and long-QT syndrome type-2 (LQT2). The prevalent 
      view has been that the loss of PM expression of hERG is attributed to 
      biosynthetic block by endoplasmic reticulum (ER) QC pathways. However, there is a 
      growing appreciation for protein QC pathways acting at post-ER cellular 
      compartments, which may contribute to conformational disease pathogenesis. This 
      article will provide a background on the structure and cellular trafficking of 
      hERG as well as inherited and acquired LQT2. We will review previous work on hERG 
      ER QC and introduce the more novel view that there is a significant peripheral QC 
      at the PM and peripheral cellular compartments. Particular attention is drawn to 
      the unique role of the peripheral QC system in acquired LQT2. Understanding the 
      QC process and players may provide targets for therapeutic intervention in 
      dealing with LQT2.
CI  - (c) 2015 The Authors. The Journal of Physiology (c) 2015 The Physiological Society.
FAU - Foo, Brian
AU  - Foo B
AD  - Department of Physiology, McGill University, Montreal, Quebec, Canada, H3G 1Y6.
FAU - Williamson, Brittany
AU  - Williamson B
AD  - Department of Biochemistry, McGill University, Montreal, Quebec, Canada, H3G 1Y6.
FAU - Young, Jason C
AU  - Young JC
AD  - Department of Biochemistry, McGill University, Montreal, Quebec, Canada, H3G 1Y6.
FAU - Lukacs, Gergely
AU  - Lukacs G
AD  - Department of Physiology, McGill University, Montreal, Quebec, Canada, H3G 1Y6.
FAU - Shrier, Alvin
AU  - Shrier A
AD  - Department of Physiology, McGill University, Montreal, Quebec, Canada, H3G 1Y6.
LA  - eng
GR  - CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20160209
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - Long Qt Syndrome 2
SB  - IM
MH  - Endoplasmic Reticulum/metabolism
MH  - *Ether-A-Go-Go Potassium Channels/genetics/metabolism
MH  - HSP70 Heat-Shock Proteins/metabolism
MH  - HSP90 Heat-Shock Proteins/metabolism
MH  - Humans
MH  - *Long QT Syndrome/genetics/metabolism
MH  - Protein Transport
PMC - PMC4850197
EDAT- 2016/01/01 06:00
MHDA- 2017/09/19 06:00
PMCR- 2017/05/01
CRDT- 2016/01/01 06:00
PHST- 2015/09/14 00:00 [received]
PHST- 2015/12/07 00:00 [accepted]
PHST- 2016/01/01 06:00 [entrez]
PHST- 2016/01/01 06:00 [pubmed]
PHST- 2017/09/19 06:00 [medline]
PHST- 2017/05/01 00:00 [pmc-release]
AID - TJP7056 [pii]
AID - 10.1113/JP270531 [doi]
PST - ppublish
SO  - J Physiol. 2016 May 1;594(9):2469-81. doi: 10.1113/JP270531. Epub 2016 Feb 9.