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

Zhi Yuan Wu, Kun Chen, Bernard Haendler, Thomas V. McDonald, Jin Song Bian

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 -6 M 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.

Original languageEnglish (US)
Pages (from-to)5061-5069
Number of pages9
JournalEndocrinology
Volume149
Issue number10
DOIs
StatePublished - Oct 2008

Fingerprint

Mitogen-Activated Protein Kinase 3
Potassium Channels
Mitogen-Activated Protein Kinase 1
Ether
Protein Isoforms
Dihydrotestosterone
Genes
Proteins
Androgen Receptors
Long QT Syndrome
human AR protein
Androgens
Proteasome Inhibitors
HEK293 Cells
Cycloheximide
Cricetulus
Lysosomes
Cardiac Myocytes
Sex Characteristics
Endoplasmic Reticulum

ASJC Scopus subject areas

  • Endocrinology

Cite this

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. / Wu, Zhi Yuan; Chen, Kun; Haendler, Bernard; McDonald, Thomas V.; Bian, Jin Song.

In: Endocrinology, Vol. 149, No. 10, 10.2008, p. 5061-5069.

Research output: Contribution to journalArticle

@article{ba9924912436489aae389dc39b733397,
title = "Stimulation of N-terminal truncated isoform of androgen receptor stabilizes human ether-{\'a}-go-go-related gene-encoded potassium channel protein via activation of extracellular signal regulated kinase 1/2",
abstract = "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-{\'a}-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 -6 M 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-{\'a}-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.",
author = "Wu, {Zhi Yuan} and Kun Chen and Bernard Haendler and McDonald, {Thomas V.} and Bian, {Jin Song}",
year = "2008",
month = "10",
doi = "10.1210/en.2007-1802",
language = "English (US)",
volume = "149",
pages = "5061--5069",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "10",

}

TY - JOUR

T1 - 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

AU - Wu, Zhi Yuan

AU - Chen, Kun

AU - Haendler, Bernard

AU - McDonald, Thomas V.

AU - Bian, Jin Song

PY - 2008/10

Y1 - 2008/10

N2 - 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 -6 M 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.

AB - 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 -6 M 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.

UR - http://www.scopus.com/inward/record.url?scp=53249090386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=53249090386&partnerID=8YFLogxK

U2 - 10.1210/en.2007-1802

DO - 10.1210/en.2007-1802

M3 - Article

VL - 149

SP - 5061

EP - 5069

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 10

ER -