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Nitric oxide and cyclic GMP Signaling in the Nervous System
My laboratory identified neuronal NADPH-diaphorase as the enzyme which produces the neural messenger nitric oxide (NO) from L-arginine. We have determined the distribution of neurons able to synthesize NO in the central and peripheral nervous system, and have begun to examine the regulation of NO synthesis in neurons in vivo. We are currently examining the NO receptor, soluble guanylyl cylase, and are identifying and characterizing targets for cyclic GMP action in the brain. We are particularly interested cGMP-stimulated phosphodiesterases, and in the regulation of protein phosphorylation by NO via the cGMP-dependent protein kinases. We have found that the release ofendogenous NO in the thalamus varies with the sleep-wake cycle, and that NO can act on thalamic neurons to regulate type II cGMP-dependent protein kinase. We are therefore interested in determining the mechanisms by which NO released from the reticular activating system can regulate consciousness.
RING Finger Proteins, Ubiquitinylation and Neural Function
The occurrence of ubiquitinylated proteins in intraneuronal deposits is one of the hallmarks of chronic neurological disease. In all the major human chronic neurodegenerative diseases (Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, motor neuron disease and Huntington's chorea) there is accumulation of intraneuronal filamentous inclusions containing ubiquitinylated proteins. Ubiquitin ligation is a multi-step process involving three main classes of enzyme. The E1 enzymes utilize ATP to form an E1-ubiquitin thioester intermediate. The activated ubiquitin is then transferred to the active cysteine of an E2 enzyme. The E3 ubiquitin protein ligase then catalyzes the transfer of the ubiquitin to a lysine residue in a target protein. Recent work indicates that a wide variety of structurally diverse RING finger proteins function as E3 ubiquitin-protein ligases. We have discovered a number of novel RING finger proteins in the brain including GERP and BERP, and are currently examining their role in ubiquitination in the nervous system.