| Title | Stimulation of androgen receptor AR45 variant stabilizes HERG potassium channel protein via activation of extracellular signal regulated kinase 1/2. | | Author(s) | Wu ZY, Chen K, Haendler B, McDonald TV, Bian JS | | Institution | From Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore; Therapeutic Research Group Oncology, Bayer Schering Pharma AG, D-13342 Berlin, Germany; Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. | | Source | Endocrinology 2008 Jul 3. | | 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), 5alpha-dihydrotestosterone (5alpha-DHT) increased HERG protein abundance in HEK293 cells stably expressing HERG in the presence of co-expressed cardiac androgen receptor variant (AR45). The elevation of HERG protein was seen in ER, Golgi and plasma membrane without clear preferential colocalization. Co-expression of the more common form of the androgen receptor did not confer 5alpha-DHT augmentation of HERG protein. Proteasome inhibitors, N-acetyl-L-leucyl-L-leucyl-L-norleucinal and MG132 prevented the 5alpha-DHT-dependent enhancement of HERG as did the lysosome inhibitor, bafilomycin A1. Consistently, the cycloheximide-based protein chase study showed that 5alpha-DHT prolonged HERG protein half-life. 5alpha-DHT/AR45 signaling induced phosphorylation of extracellular signaling regulated kinase (ERK1/2). Blockade of ERK1/2 with PD98059 and U0126 prevented the effect of androgen on HERG protein abundance. Functional studies showed that 5alpha-DHT treatment for 24 h increased HERG K(+) current density in CHO cells co-transfected with cDNAs of AR45 and HERG channels. Moreover, 5alpha-DHT also increased ERG protein abundance in isolated rabbit cardiac myocytes. In conclusion, these data provide evidence that stimulation of AR45 receptors by androgens upregulates 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18599551 |
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