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doi: 10.1242/10.1242/jcs.00183

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Nitric oxide signaling specificity — the heart of the problem

Department of Physiology, University of California at San Francisco School of Medicine, 513 Parnassus Avenue, San Francisco, CA 94143-0444, USA

View larger version (19K): [in a new window]   Fig. 1. Skeletal-muscle-derived NO enhances blood flow to contracting muscle. nNOSµ occurs at the skeletal muscle plasma membrane as a component of the dystrophin glycoprotein complex. The PDZ domain (pink) from nNOS binds to the PDZ domain of syntrophin (Syn), which independently binds to both dystrophin and dystrobrevin. Dystrophin itself adheres to the membrane by binding to glycoproteins such as dystroglycan (DG). Skeletal-muscle-derived NO diffuses to adjacent blood vessels to increase perfusion of contracting muscle.

View larger version (15K): [in a new window]   Fig. 2. Protein interactions regulating NO signaling at neuronal synapses. PDZ domain interactions (pink) function to bring nNOS to the NMDA receptor, allowing specific activation of nNOS in response to glutamate-induced calcium influx. Binding of nNOS to PSD-95 leaves the nNOS PDZ domain peptide-binding pocket free to interact with other proteins such as Capon. The NO produced in association with NMDA receptor activity diffuses to presynaptic nerve terminals and nitrosylates Dexras associated with Capon. Abbreviations: Arg, arginine; CaM, calmodulin; GK, guanylate kinase domain.

View larger version (15K): [in a new window]   Fig. 3. Regulation of eNOS in caveolae. Myristoylation and palmitoylation (jagged lines) target eNOS to plasma membrane caveolae. Interaction with caveolin inhibits eNOS activity. Endothelial cell stimuli such as shear stress, recruit Hsp90 and activate eNOS by recruiting calcium and calmodulin (CaM). Phosphorylation of eNOS by Akt also increases activity.

View larger version (15K): [in a new window]   Fig. 4. Opposing roles for eNOS and nNOS in regulating heart contraction. NO formed by eNOS inhibits L-type voltage-dependent calcium channels (VDCC) to decrease muscle contraction. By contrast, NO produced by nNOS on the sarcoplasmic reticulum stimulates calcium influx through the ryanodine receptor (RyR) to augment cardiac contractility.