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J. Biol. Chem., Vol. 280, Issue 35, 30814-30828, September 2, 2005

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Angiotensin II Inhibits bTREK-1 K⁺ Channels in Adrenocortical Cells by Separate Ca²⁺- and ATP Hydrolysis-dependent Mechanisms^*

John J. Enyeart, Sanjay J. Danthi¶||, Haiyan Liu, and Judith A. Enyeart

From the Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210-1239 and ^¶The Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio 43210

Bovine adrenocortical cells express bTREK-1 K⁺ channels that set the resting membrane potential (V_m) and couple angiotensin II (AngII) and adrenocorticotropic hormone (ACTH) receptors to membrane depolarization and corticosteroid secretion. In this study, it was discovered that AngII inhibits bTREK-1 by separate Ca²⁺- and ATP hydrolysis-dependent signaling pathways. When whole cell patch clamp recordings were made with pipette solutions that support activation of both Ca²⁺- and ATP-dependent pathways, AngII was significantly more potent and effective at inhibiting bTREK-1 and depolarizing adrenal zona fasciculata cells, than when either pathway is activated separately. External ATP also inhibited bTREK-1 through these two pathways, but ACTH displayed no Ca²⁺-dependent inhibition. AngII-mediated inhibition of bTREK-1 through the novel Ca²⁺-dependent pathway was blocked by the AT₁ receptor antagonist losartan, or by including guanosine-5'-O-(2-thiodiphosphate) in the pipette solution. The Ca²⁺-dependent inhibition of bTREK-1 by AngII was blunted in the absence of external Ca²⁺ or by including the phospholipase C antagonist U73122, the inositol 1,4,5-trisphosphate receptor antagonist 2-amino-ethoxydiphenyl borate, or a calmodulin inhibitory peptide in the pipette solution. The activity of unitary bTREK-1 channels in inside-out patches from adrenal zona fasciculata cells was inhibited by application of Ca²⁺ (5 or 10 µM) to the cytoplasmic membrane surface. The Ca²⁺ ionophore ionomycin also inhibited bTREK-1 currents through channels expressed in CHO-K1 cells. These results demonstrate that AngII and selected paracrine factors that act through phospholipase C inhibit bTREK-1 in adrenocortical cells through simultaneous activation of separate Ca²⁺- and ATP hydrolysis-dependent signaling pathways, providing for efficient membrane depolarization. The novel Ca²⁺-dependent pathway is distinctive in its lack of ATP dependence, and is clearly different from the calmodulin kinase-dependent mechanism by which AngII modulates T-type Ca²⁺ channels in these cells.

Received for publication, April 19, 2005 , and in revised form, June 30, 2005.

^* This work was supported in part by National Institutes of Health Grant R01-DK47875 (to J. J. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Supported in part by the National Science Foundation under agreement 0112050.

To whom correspondence should be addressed: Dept. of Neuroscience, Ohio State University College of Medicine and Public Health, 5196 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210-1239. Tel.: 614-292-3511; E-mail: enyeart.1{at}osu.edu.

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