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(Hypertension. 2000;36:116-a.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Effects of the N-Terminal Sequence of ACE on the Properties of Its C-Domain

Branislav Marcic; Peter A. Deddish; Herbert L. Jackman; Ervin G. Erdös; Fulong Tan

From the Departments of Pharmacology (B.M., P.A.D., H.L.J., E.G.E., F.T.) and Anesthesiology (E.G.E., F.T.), University of Illinois College of Medicine at Chicago.

Correspondence to Ervin G. Erdös, MD, Dept of Pharmacology (M/C 868), University of Illinois-Chicago, 835 S Wolcott Ave, Chicago, IL 60612. E-mail EGErdos{at}uic.edu

Abstract—Angiotensin I–converting enzyme (ACE, kininase II) has 2 active domains (N and C) in a single peptide chain. Because we found its N-domain more stable than its C-domain, we investigated the effect of the amino-terminus of human ACE on the C-domain with a molecular construct expressed in Chinese hamster ovary cells (CHO) cells and transiently in HEK293 cells. This active N-deleted ACE contained only the first 141 amino acids of the human N-domain but not its active center and was linked to the active C-domain containing the transmembrane and cytosolic portions of ACE. The CHO cells were also transfected with human B₂ bradykinin receptor. ACE inhibitors (5 nmol/L or 1 µmol/L) augmented bradykinin (100 nmol/L) effects, elevated B₂ receptor numbers, and resensitized the receptor desensitized by agonist as measured by arachidonic acid release or [Ca²⁺]_i mobilization. Arachidonic acid release was mediated by pertussis toxin–sensitive G_i, and [Ca²⁺]_i mobilization was mediated by pertussis-insensitive G_q protein receptor complex. The properties of the construct were compared with wild-type ACE and separate N- and C-domains. The N-deleted ACE differed from wild-type in activation by Cl^- and [SO₄]^2- ions, hydrolysis ratios of substrates (both short synthetic and endogenous peptides) and heat stability. Thus, the N-terminal peptide of ACE affected the characteristics of the C-domain active center. ACE inhibitors acting on N-deleted ACE, which had only a single C-domain active center anchored to plasma membrane, induced cross-talk between the enzyme and the B₂ receptor (eg, the inhibitors resensitized the receptor) independent of blocking bradykinin inactivation.

Key Words: angiotensin • bradykinin • angiotensin-converting enzyme inhibitors • receptors, bradykinin • arachidonic acid • calcium

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