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(Hypertension. 2005;46:1140.)
© 2005 American Heart Association, Inc.

Original Articles

Intracellular Signaling for Vasoconstrictor Coupling Factor 6

Novel Function of ß-Subunit of ATP Synthase as Receptor

Tomohiro Osanai; Koji Magota; Makoto Tanaka; Michiko Shimada; Reiichi Murakami; Satoko Sasaki; Hirofumi Tomita; Naotaka Maeda; Ken Okumura

From the Second Department of Internal Medicine (T.O., M.T., M.S., R.M., S.S., H.T., N.M, K.O.), Hirosaki University School of Medicine, Hirosaki, Japan; Daiichi Suntory Biomedical Research Co, Ltd (K.M.), Osaka, Japan.

Correspondence to Tomohiro Osanai, MD, the Second Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562 Japan. E-mail osanait{at}cc.hirosaki-u.ac.jp

Coupling factor 6 (CF6), a component of adenosine triphosphate (ATP) synthase, is circulating and functions as an endogenous vasoconstrictor by inhibiting cytosolic phospholipase A₂. We showed a high plasma level of CF6 in human hypertension. The present study focused on the identification and characterization of a receptor for CF6 and its post-receptor signaling pathway. Incubation of human umbilical vein endothelial cells (HUVECs) with an excess of free CF6 reduced by 50% the immunoreactivity for the antibody to ß-subunit of ATP synthase at the cell surface, but unaffected that for the -subunit antibody. A significant displacement of radioligand was observed at 3x10^–9 through 10^–7 M unlabeled CF6, and the Kd was 7.6 nM. Adenosine diphosphate (ADP) at 10^–7 M and ß-subunit antibody suppressed the binding of ¹²⁵I-CF6 by 81.3±9.7% and 32.0±2.0%, respectively, whereas the -subunit antibody unaffected it. The hydrolysis activity of ATP to ADP was increased by 1.6-fold by CF6 at 10^–7 M, and efrapeptin at 10^–5 M, an inhibitor of ATP synthase, blocked it. CF6 at 10^–7 M decreased intracellular pH in 2',7'-bis(carboxyethyl-5 (6))-carboxyfluorescein-loaded HUVEC. Amyloride at 10^–4 M augmented the pH decrease in response to CF6, whereas efrapeptin at 10^–5 M blocked it. Arachidonic acid release was suppressed by CF6, and it was reversed by efrapeptin at 10^–5 M or ß-subunit antibody or ADP at 10^–7 M. The ß-subunit antibody suppressed coupling factor 6–induced increase in blood pressure. These indicate that membrane-bound ATP synthase functions as a receptor for CF6 and may have a previously unsuspected role in the genesis of hypertension by modulating the concentration of intracellular hydrogen.

Key Words: hypertension • prostacyclin

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Vasoconstriction Caused by the ATP Synthase Subunit–Coupling Factor 6: A New Function for a Historical Enzyme

Stephanie W. Watts
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