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J. Biol. Chem., Vol. 279, Issue 39, 40938-40945, September 24, 2004

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Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration^*

Kousaku Iwatsubo, Susumu Minamisawa, Takashi Tsunematsu, Masamichi Nakagome, Yoshiyuki Toya, James E. Tomlinson, Satoshi Umemura, Robert M. Scarborough, Daniel E. Levy¶, and Yoshihiro Ishikawa||**

From the Departments of Physiology and Medicine, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Portola Pharmaceuticals Inc., South San Francisco, California 94080, ^¶Scios, Inc., Fremont, California 94555, and the ^||Departments of Cell Biology and Molecular Medicine, and Medicine (Cardiology), University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Adenylyl cyclase, a major target enzyme of -adrenergic receptor signals, is potently and directly inhibited by P-site inhibitors, classic inhibitors of this enzyme, when the enzyme catalytic activity is high. Unlike -adrenergic receptor antagonists, this is a non- or uncompetitive inhibition with respect to ATP. We have examined whether we can utilize this enzymatic property to regulate the effects of -adrenergic receptor stimulation differentially. After screening multiple new and classic compounds, we found that some compounds, including 1R,4R-3-(6-aminopurin-9-yl)-cyclopentanecarboxylic acid hydroxyamide, potently inhibited type 5 adenylyl cyclase, the major cardiac isoform, but not other isoforms. In normal mouse cardiac myocytes, contraction induced by low -adrenergic receptor stimulation was poorly inhibited with this compound, but the induction of cardiac myocyte apoptosis by high -adrenergic receptor stimulation was effectively prevented by type 5 adenylyl cyclase inhibitors. In contrast, when cardiac myocytes from type 5 adenylyl cyclase knock-out mice were examined, -adrenergic stimulation poorly induced apoptosis. Our data suggest that the inhibition of -adrenergic signaling at the level of the type 5 adenylyl cyclase isoform by P-site inhibitors may serve as an effective method to prevent cardiac myocyte apoptosis induced by excessive -adrenergic stimulation without deleterious effect on cardiac myocyte contraction.

Received for publication, December 29, 2003 , and in revised form, July 12, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Cardiovascular Research Institute, Dept. of Cell Biology and Molecular Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 S. Orange Ave., Newark, NJ 07103. E-mail: ishikayo{at}umdnj.edu.

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