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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

Department of Pharmacology (Z.-Y.W., K.C., J.-S.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Therapeutic Research Group Oncology (B.H.), Bayer Schering Pharma AG, D-13342 Berlin, Germany; and Departments of Medicine and Molecular Pharmacology (T.V.M.), Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: Jin-Song Bian, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. E-mail: phcbjs{at}nus.edu.sg.

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), 5-dihydrotestosterone (5-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 5-DHT augmentation of HERG protein. Proteasome inhibitors, N-acetyl-L-leucyl-L-leucyl-L-norleucinal and MG132 prevented the 5-DHT- dependent enhancement of HERG, as did the lysosome inhibitor, bafilomycin A1. Consistently, the cycloheximide-based protein chase study showed that 5-DHT prolonged HERG protein half-life. 5-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 5-DHT treatment for 24 h increased HERG K⁺ current density in Chinese hamster ovary cells cotransfected with cDNAs of AR45 and HERG channels. Moreover, 5-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.