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,1
Laboratory of Peptide Research, Departments of
* Pharmacology,
Anesthesiology, and
Anatomy and Cell Biology, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA
1Correspondence: Department of Pharmacology (MC 868), 835 S. Wolcott Rm. E403, Chicago, IL 60612, USA. E-mail: egerdos{at}uic.edu
To investigate how angiotensin I-converting enzyme (ACE) inhibitors enhance the actions of bradykinin (BK) on B2 receptors independent of blocking BK inactivation, we expressed human somatic ACE and B2 receptors in CHO cells. Bradykinin and its ACE-resistant analog were the receptor agonists. B2 fused with green fluorescent protein (GFP) and ACE were coprecipitated with antisera to GFP or ACE shown in Western blots. Immunohistochemistry of fixed cells localized ACE by red color and B2-GFP by green. Yellow on plasma membranes of coexpressing cells also indicated enzyme-receptor complex formation. Using ACE-fused cyan fluorescent protein donor and B2-fused yellow fluorescent protein (YFP) acceptor, we registered fluorescence resonance energy transfer (FRET) by the enhanced fluorescence of donor on acceptor photobleaching, establishing close (within 10 nm) positions of B2 receptors and ACE. Bradykinin stimulation cointernalized ACE and B2 receptors. We expressed ACE fused to N terminus of B2 receptors, anchoring only receptors to plasma membranes. Here, in contrast to cells, where both ACE and B2 receptors are separately anchored, ACE inhibitors neither enhance activation of chimeric B2 nor resensitize desensitized B2 receptors. Heterodimer formation between ACE and B2 receptors can be a mechanism for ACE inhibitors to augment kinin activity at cellular level.—Chen, Z., Deddish, P. A., Minshall, R. D., Becker, R. P., Erdös, E. G., Tan, F. Human ACE and bradykinin B2 receptors form a complex at the plasma membrane.
Key Words: oligomer • FRET • converting enzyme • peptide receptors • kinins
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