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Corticotropin Induces the Expression of TREK-1 mRNA and K⁺ Current in Adrenocortical Cells

Department of Neuroscience, the Ohio State University, College of Medicine, Columbus, Ohio

Bovine adrenal zona fasciculata (AZF) cells express a two-pore/four-transmembrane segment bTREK-1 K⁺ channel that sets the resting potential and couples hormonal signals to depolarization-dependent Ca²⁺ entry and cortisol secretion. It was discovered that corticotropin (1–2000 pM) enhances the expression of bTREK-1 mRNA and membrane current in cultured AZF cells. Forskolin and 8-pcpt-cAMP mimicked corticotropin induction of bTREK-1 mRNA, but angiotensin II (AII) was ineffective. The induction of bTREK-1 mRNA by corticotropin was partially blocked by the A-kinase antagonist H-89. 8-(4-Chloro-phenylthio)-2-O-methyladenosine-3'-5'-cyclic monophosphate, a cAMP analog that activates cAMP-regulated guanine nucleotide exchange factors (Epac), failed to increase bTREK-1 mRNA. Corticotropin-stimulated increases in bTREK-1 mRNA were eliminated by inhibitors of protein synthesis or gene transcription. bTREK-1 current disappeared after 24 h in serum-supplemented medium, but in the presence of corticotropin, bTREK-1 expression was maintained for at least 48 h. The enhancement of bTREK-1 mRNA and ionic current contrasts with the corticotropin-induced down-regulation of the Kv1.4 voltage-gated K⁺ current and associated mRNA in AZF cells. These results demonstrate that corticotropin rapidly and potently induces the expression of bTREK-1 in AZF cells at the pretranslational level by a cAMP-dependent mechanism that is partially dependent on A-kinase but independent of Epac and Ca²⁺. They further indicate that prolonged stimulation of AZF cells by corticotropin, as occurs during long-term stress or disease, may produce pronounced changes in the expression of genes encoding ion channels, thereby reshaping the electrical properties of these cells to enhance or limit cortisol secretion.

Address correspondence to: Dr. John J. Enyeart, Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5190 Graves Hall, 333 W. 10th Avenue, Columbus, OH 43210-1239. E-mail: enyeart.1{at}osu.edu

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