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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Angiotensin II inhibits native bTREK-1 K⁺ channels through a PLC-, kinase C-, and PIP₂-independent pathway requiring ATP hydrolysis

Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, Ohio

Submitted 16 January 2007 ; accepted in final form 4 May 2007

Angiotensin II (ANG II) inhibits bTREK-1 (bovine KCNK2) K⁺ channels in bovine adrenocortical cells through a Gq-coupled AT₁ receptor by activation of separate Ca²⁺- and ATP hydrolysis-dependent signaling pathways. Whole cell patch-clamp recording from bovine adrenal zona fasciculata (AZF) cells was used to characterize the ATP-dependent signaling mechanism for inhibition of bTREK-1 by ANG II. We discovered that ATP-dependent inhibition of bTREK-1 by ANG II occurred through a novel mechanism that was independent of PLC and its established downstream effectors. The ATP-dependent inhibition of bTREK-1 by ANG II was not reduced by the PLC antagonists edelfosine and U73122 [GenBank] , or by the PKC antagonists bisindolylmaleimide I (BIM) or calphostin C. bTREK-1 was partially inhibited (25%) by the PKC activator phorbol 12,13 dibutyrate (PDBu) through an ATP-dependent mechanism that was blocked by BIM. Addition of Phosphatidylinositol(4,5) bisphosphate diC8 [DiC₈PI(4,5)P₂], a water-soluble derivative of phosphotidyl inositol 4,5 bisphosphate (PIP₂) to the pipette solution failed to alter inhibition by ANG II. bTREK-1 inhibition by ANG II was also insensitive to antagonists of other protein kinases activated by ANG II in adrenocortical cells but was completely blocked by inorganic polytriphosphate PPPi. DiC₈PI(4,5)P₂ was a weak activator of bTREK-1 channels, compared with the high-affinity ATP analog N⁶-(2-phenylethyl)adenosine-5'-O-triphosphate (6-PhEt-ATP). These results demonstrate that the modulation of bTREK-1 channels in bovine AZF cells is distinctive with respect to activation by phosphoinositides and nucleotides and inhibition by Gq-coupled receptors. Importantly, ANG II inhibits bTREK-1 channels through a novel pathway that is different from that described for inhibition of native TREK-1 channels in neurons, or cloned channels expressed in cell lines. They also indicate that, under physiological conditions, ANG II inhibits bTREK-1 and depolarizes AZF cells by two, novel, independent pathways that diverge proximal to the activation of PLC.

adrenal cortex; ion channels; patch clamp

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				H. Liu, J. A. Enyeart, and J. J. Enyeart ACTH Inhibits bTREK-1 K+ Channels through Multiple cAMP-dependent Signaling Pathways J. Gen. Physiol., August 1, 2008; 132(2): 279 - 294. [Abstract] [Full Text] [PDF]