scholarly journals Stimulation of N-Terminal Truncated Isoform of Androgen Receptor Stabilizes Human Ether-á-go-go-Related Gene-Encoded Potassium Channel Protein via Activation of Extracellular Signal Regulated Kinase 1/2

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5061-5069 ◽  
Author(s):  
Zhi-Yuan Wu ◽  
Kun Chen ◽  
Bernard Haendler ◽  
Thomas V. McDonald ◽  
Jin-Song Bian
Keyword(s):  
Androgen Receptor ◽  
Long Qt Syndrome ◽  
Hek293 Cells ◽  
K Channel ◽  
Protein Abundance ◽  
Related Gene ◽  
Long Qt ◽  
Channel Protein ◽  
Qt Syndrome ◽  
Stimulation Of

Proarrhythmic drugs induce long QT syndrome more frequently in women than men. The present study was designed to determine whether androgens regulate the function and expression of the human ether-á-go-go-related gene (HERG) encoded K+ channel, which is largely responsible for determining the QT interval. In a concentration-dependent manner (10−9 to 10−6m for 24 h), 5α-dihydrotestosterone (5α-DHT) increased HERG protein abundance in HEK293 cells stably expressing HERG in the presence of coexpressed cardiac androgen receptor (AR) variant [N-terminal truncated isoform of AR (AR45)]. The elevation of HERG protein was seen in endoplasmic reticulum, Golgi, and plasma membrane without clear preferential colocalization. Coexpression of the more common form of the AR did not confer 5α-DHT augmentation of HERG protein. Proteasome inhibitors, N-acetyl-L-leucyl-L-leucyl-L-norleucinal and MG132 prevented the 5α-DHT- dependent enhancement of HERG, as did the lysosome inhibitor, bafilomycin A1. Consistently, the cycloheximide-based protein chase study showed that 5α-DHT prolonged HERG protein half-life. 5α-DHT/AR45 signaling induced phosphorylation of ERK1/2. Blockade of ERK1/2 with PD98059 and U0126 prevented the effect of androgen on HERG protein abundance. Functional studies showed that 5α-DHT treatment for 24 h increased HERG K+ current density in Chinese hamster ovary cells cotransfected with cDNAs of AR45 and HERG channels. Moreover, 5α-DHT also increased ether-á-go-go-related gene-encoded K+ channel protein abundance in isolated rabbit cardiac myocytes. In conclusion, these data provide evidence that stimulation of AR45 receptors by androgens up-regulates HERG K+ channel abundance and activity mainly through stabilizing HERG protein in an ERK1/2 dependent mechanism, and suggest a mechanism to explain the sex difference in the long QT syndrome.

scholarly journals Disruption of Protein Quality Control of Human Ether-à-go-go Related Gene K+ Channel Results in Profound Long QT Syndrome

Heart Rhythm ◽  
2021 ◽  
Author(s):  
Hannah A. Ledford ◽  
Lu Ren ◽  
Phung N. Thai ◽  
Seojin Park ◽  
Valeriy Timofeyev ◽  
...  
Keyword(s):  
Quality Control ◽  
Long Qt Syndrome ◽  
Protein Quality ◽  
Protein Quality Control ◽  
K Channel ◽  
Related Gene ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1144
Author(s):  
Makoto Ono ◽  
Don E. Burgess ◽  
Elizabeth A. Schroder ◽  
Claude S. Elayi ◽  
Corey L. Anderson ◽  
...  
Keyword(s):  
Cell Surface ◽  
Long Qt Syndrome ◽  
Molecular Mechanisms ◽  
Surface Membrane ◽  
Long Qt ◽  
Cell Surface Membrane ◽  
Channel Protein ◽  
Channel Proteins ◽  
Qt Syndrome

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2.

scholarly journals Fluconazole-induced long QT syndrome via impaired human ether-a-go-go-related gene (hERG) protein trafficking in rabbits

EP Europace ◽  
2016 ◽  
pp. euw091
Author(s):  
Jinli Wang ◽  
Guan Wang ◽  
Xiaoqing Quan ◽  
Lei Ruan ◽  
Yang Liu ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Protein Trafficking ◽  
Related Gene ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Mutant MiRP1 subunits modulate HERG K+ channel gating: a mechanism for pro-arrhythmia in long QT syndrome type 6

2003 ◽  
Vol 551 (1) ◽  
pp. 253-262 ◽  
Author(s):  
Y. Lu ◽  
M. P Mahaut-Smith ◽  
C. L-H Huang ◽  
J. I Vandenberg
Keyword(s):  
Long Qt Syndrome ◽  
Channel Gating ◽  
K Channel ◽  
Syndrome Type ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Recurrent Pregnancy Loss and Concealed Long‐QT Syndrome

2021 ◽  
Author(s):  
Laura Kasak ◽  
Kristiina Rull ◽  
Tao Yang ◽  
Dan M. Roden ◽  
Maris Laan
Keyword(s):  
Long Qt Syndrome ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Chromosomal Abnormalities ◽  
Fetal Loss ◽  
K Channel ◽  
Long Qt ◽  
Maternal Risk ◽  
Qt Syndrome

Background Recurrent pregnancy loss affects 1% to 2% of couples attempting childbirth. A large fraction of all cases remains idiopathic, which warrants research into monogenic causes of this distressing disorder. Methods and Results We investigated a nonconsanguineous Estonian family who had experienced 5 live births, intersected by 3 early pregnancy losses, and 6 fetal deaths, 3 of which occurred during the second trimester. No fetal malformations were described at the autopsies performed in 3 of 6 cases of fetal death. Parental and fetal chromosomal abnormalities (including submicroscopic) and maternal risk factors were excluded. Material for genetic testing was available from 4 miscarried cases (gestational weeks 11, 14, 17, and 18). Exome sequencing in 3 pregnancy losses and the mother identified no rare variants explicitly shared by the miscarried conceptuses. However, the mother and 2 pregnancy losses carried a heterozygous nonsynonymous variant, resulting in p.Val173Asp ( rs199472695 ) in the ion channel gene KCNQ1 . It is expressed not only in heart, where mutations cause type 1 long‐QT syndrome, but also in other tissues, including uterus. The p.Val173Asp variant has been previously identified in a patient with type 1 long‐QT syndrome, but not reported in the Genome Aggregation Database. With heterologous expression in CHO cells, our in vitro electrophysiologic studies indicated that the mutant slowly activating voltage‐gated K+ channel ( I Ks ) is dysfunctional. It showed reduced total activating and deactivating currents ( P <0.01), with dramatically positive shift of voltage dependence of activation by ≈10 mV ( P <0.05). Conclusions The current study uncovered concealed maternal type 1 long‐QT syndrome as a potential novel cause behind recurrent fetal loss.

scholarly journals Electrophysiological action of K-channel opener nicorandil to the patients with congenital long QT syndrome and canine model of long QT syndrome.

1999 ◽  
Vol 19 (2) ◽  
pp. 153-160
Author(s):  
Masaomi Chinushi ◽  
Hirohide Uchiyama ◽  
Hiroshi Furushima ◽  
Hirohide Kasai ◽  
Takashi Washizuka ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Canine Model ◽  
K Channel ◽  
Long Qt ◽  
Channel Opener ◽  
Qt Syndrome ◽  
K Channel Opener ◽  
Congenital Long Qt Syndrome
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