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(Hypertension. 2004;44:963.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Cyclophilin A Functions as an Endogenous Inhibitor for Membrane-Bound Guanylate Cyclase-A

Zi-Jiang Chen; Michael Vetter; Geen-Dong Chang; Shiguo Liu; Danian Che; Yaxian Ding; Sung Soo Kim; Chung-Ho Chang

From the Department of Medicine (Z-J.C., M.V., S.L., D.C., Y.D., C-H.C.), Case Western Reserve University and University Hospital of Cleveland, Ohio; Department of Medicine (Z-J.C.), Reproductive Research Center, Shandong Provincial Hospital, Shandong University, Jinan, P.R. China; Graduate Institute of Biochemical Sciences (G-D.C.), National Taiwan University, Taipei, Taiwan; and Department of Molecular Biology (S.S.K.), Kyung Hee University, Seoul, Korea.

Correspondence to Chung-Ho Chang, Department of Medicine, Division of Hypertension, School of Medicine W165, Cleveland, OH 44106. E-mail cxc13{at}po.cwru.edu

Cyclophilin A (CypA), a receptor for the immunosuppressive agent cyclosporin A, is a cis-trans-peptidyl-prolyl isomerase (PPIase). It accelerates the cis-trans isomerization of prolyl-peptide bonds. CypA binds and regulates the activity of a variety of proteins. Atrial natriuretic factor (ANF) and its receptor membrane-bound guanylate cyclase-A (GC-A) are involved in the regulation of blood pressure. We examined whether CypA affects the activation of GC-A by ANF. The results showed that CypA associated with GC-A. Interestingly, binding of ANF to GC-A released CypA. Transfection of CypA inhibited ANF-stimulated GC-A activity, indicating that CypA functions as an endogenous inhibitor for GC-A activation. CypA also inhibits the activity of guanylate cyclase-C (GC-c), the catalytic domain of GC-A, indicating that CypA interacts with the catalytic domain of GC-A. In contrast, transfection of CypA R55A, a CypA mutant expressing low PPIase activity, did not significantly attenuate the activity of GC-c and the activation of GC-A. Inhibition of PPIase activity of CypA with cyclosporin A also blocks the inhibitory effect of CypA on GC-c activity. These results demonstrate that PPIase activity is required for CypA to inhibit GC-c activity and GC-A activation by ANF. Furthermore, mutation of Pro 822, 902, or 958 in GC-c abolished its activity. Therefore, it is likely that CypA binds to GC-A and catalyzes the cis-trans isomerization of Pro 822, 902, or 958, which keeps GC-A in the inactive state, and that binding of ANF to GC-A alters the conformation of the catalytic domain that releases CypA from GC-A leading to enzyme activation.

Key Words: cyclosporin • cyclic GMP

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