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Information processing in the brain reflects communication among neurons via neurotransmitters. The major chemical classes of neurotransmitters are biogenic amines, amino acids and peptides. During the past few years we have identified and characterized novel transmitters or neuromodulators which overturn much dogma in the field. For instance, we discovered that nitric oxide (NO) satisfies the major criteria of a neurotransmitter, as NO synthase is localized to specific neuronal populations and inhibitors of the enzyme block neurotransmission in certain systems. Yet NO is a gas which cannot be stored in synaptic vesicles, released by exocytosis, or act at receptor proteins on cell membranes. In vascular stroke excess release of the excitatory amino acid neurotransmitter glutamate activates NO synthase to form NO that mediates neurotoxicity. Evidence for this includes the blockade of stroke damage by inhibitors of NO synthase and a lesser amount of stroke damage in the brains of mice lacking the neuronal form of NO synthase. In mice in which the gene for the neuronal NO synthase has been "knocked out" we observe dramatic alterations in social and sexual behavior indicating a prominent role for NO in aggression and sexual attraction. At least one other gas, carbon monoxide (CO) may be a neurotransmitter. CO is formed by the action of the enzyme heme oxygenase, which cleaves the heme ring liberating CO and forming biliverdin, which is converted to bilirubin. We found that a neuronal form of heme oxygenase occurs in discrete neuronal populations in the brain, and CO formed from it may be involved in regulating levels of cyclic GMP. Just as NO, formed in the endothelial layer of blood vessels, diffuses to the smooth muscle and is a major normal relaxing element of blood vessels, CO is formed by heme oxygenase in the endothelium and also relaxes blood vessels. Besides forming CO, heme oxygenase action gives rise to ferrous iron and biliverdin which is rapidly reduced to bilirubin. We have shown that bilirubin is a key neuronal antioxidant neuroprotectant. Low nanomolar concentrations of bilirubin reverse the oxidant effects of 10,000 times higher concentrations of oxidants, an amplification mediated by a unique bilverdin reductase cycle. When bilirubin acts as an antioxidant, it is oxidized to biliverdin. Biliverdin reductase rapidly reforms bilirubin. Deletion of biliverdin reductase from cells leads to excess oxidation and cell death. D-serine may be a neurotransmitter, as improbable as the gases, being the "wrong" isomer and occurring in glia, not neurons. Levels of D-serine in the brain are a third those of L-serine, and it is the only D-amino acid to occur in substantial levels in the brain. Our immunohistochemical maps reveal D-serine in a unique population of glia, which ensheathe nerve terminals selectively in regions of the brain enriched in the subtype of glutamate receptor referred to as the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors had been thought to be co-activated by the amino acids glycine and glutamate. D-Serine appears to be the normal stimulus for the glycine site of this receptor. D-Serine is released from these astrocytes by glutamate acting at the AMPA subtype of receptor. Selective destruction of D-serine by D-amino acid oxidase markedly reduces NMDA neurotransmission. A novel enzyme, serine racemase, transforms L- to D-serine. It binds to GRIP, a scaffolding protein that links serine racemase to AMPA receptors so that glutamate transmission markedly activate the enzyme with associated release of D-serine.
Patterson, Randen L., van Rossum, Damian B., Ford, Diana L., Hurt, Kenneth J., Bae, Sun Sik, Suh, Pann-Ghill, Kurosaki, Tomohiro, Snyder, Solomon H. and Gill, Donald, L., Phospholipase C-y Is Required for Agonist-Induced Ca2+ Entry. Cell, Vol. 111, pp.529-541, 2002.
Baranano, David E., Rao, Mahil, Ferris, Christopher D. and Snyder, Solomon H., Biliverdin Reductase: A Major Physiologic Cytoprotectant. PNAS, Vol. 99, pp.16093-16098, 2002.
Snyder, Solomon H., Forty Years of Neurotransmitters. Arch Gen Psychiatry, Vol. 59, 2002. Sawa, Akira and Snyder, Solomon H., Schizophrenia: Diverse Approaches to a Complex Disease. Science, Vol. 296, pp.692-695, 2002.