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Vol. 54, Issue 2, 305-312, August 1998

Neuronal Nitric Oxide Synthase Isoforms alpha  and µ Are Closely Related Calpain-Sensitive Proteins

Romuald Lainé and Paul R. Ortiz de Montellano

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-0446

The neuronal nitric oxide synthase isoform nNOSµ, which is expressed in striated muscle, differs from nNOSalpha , the major brain isoform, by the insertion of 34 amino acid residues between the calmodulin- and flavin-binding domains [J Biol Chem 271:11204-11208 (1996)]. We show here that recombinant, purified nNOSµ, despite the peptide insertion, has the same spectroscopic properties, L-arginine kcat and Km values, optimal pH, and calmodulin binding affinity constant as nNOSalpha . However, nNOSµ consumes NADPH and reduces cytochrome c at approximately half the rate of nNOSalpha . The rates of degradation of the two proteins by rat brain and muscle homogenates show that nNOSµ is degraded more slowly than nNOSalpha . The in vitro half-lives of nNOSalpha and nNOSµ are 12 and 50 min, respectively, and calpain is important for this degradation. These short in vitro half-lives suggest that the nNOS isoforms are susceptible to rapid degradation in vivo. The elevated (20-fold) levels of calpain in diseased muscle tissue in Duchenne muscular dystrophy, and the hydrolytic sensitivity of both nNOSµ and nNOSalpha to this enzyme, may contribute to the deficiency of nNOS activity in the diseased tissue.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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