PT  - JOURNAL ARTICLE
AU  - Jian Chen
AU  - Kun Chen
AU  - Jakub Sroubek
AU  - Zhi-Yuan Wu
AU  - Dierk Thomas
AU  - Jin-Song Bian
AU  - Thomas V. McDonald
TI  - Post-Transcriptional Control of Human Ether-a-go-go-Related Gene Potassium Channel Protein by α-Adrenergic Receptor Stimulation
AID  - 10.1124/mol.109.062216
DP  - 2010 Aug 01
TA  - Molecular Pharmacology
PG  - 186--197
VI  - 78
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/78/2/186.short
4100  - http://molpharm.aspetjournals.org/content/78/2/186.full
SO  - Mol Pharmacol2010 Aug 01; 78
AB  - Stimulation of α1-adrenoreceptors (α1-AR) acutely alters ion channel behavior via several signaling pathways [calcium and protein kinase C (PKC)]. Little is known about sustained α1-adrenergic/PKC signaling and channel regulation as may occur during cardiovascular disease states. Here we describe the effects of prolonged α1A-AR and PKC activity on human ether-a-go-go-related gene (HERG) K+ channels (Kv11.1) expressed in a heterologous expression system. Stimulation of α1A-AR with phenylephrine or direct activation of PKC with phorbol ester increased HERG channel protein abundance and K+ current density in a time- and dose-dependent manner. Channel augmentation reached a steady-state plateau within 24 h with a 2- to 6-fold induction. Phorbol ester and moderate α1A-AR stimulation enhanced HERG abundance in a PKC-dependent fashion but with stronger α1A-adrenergic stimulation; protein kinase A (PKA)-dependent activity also contributed. Comparable channel induction of other cardiac K+ channels was not seen in this system. Comparison of wild-type HERG and channels with either mutated PKC phosphorylation sites (HERGΔPKC) or mutated PKA phosphorylation sites (HERGΔPKA) suggested that the mechanisms of augmentation of HERG by the two kinases were partially overlapping. The PKC-dependent effect was largely due to enhanced synthetic rates. Stimulation of α1-AR in cultured rat neonatal cardiac myocytes also enhanced the abundance of ERG channels. These findings show that α1A-AR stimulation is capable of influencing the balance of HERG channel synthesis and degradation via multiple signaling pathways, a process that may have relevance in cardiac diseases and treatment.